Pyrazoles

ABSTRACT

The invention relates to pyrazole derivatives which are NMDA NR2B receptor inhibitors, useful in treating central nervous system diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase of International Application No.PCT/US2015/045413 filed on Aug. 14, 2015, which claims the benefit ofU.S. Provisional Application No. 62/037,815, which was filed on Aug. 15,2014; and U.S. Provisional Application No. 62/146,629, which was filedon Apr. 13, 2015, each of which is incorporated herein by reference inits entirety.

TECHNICAL FIELD

The invention relates pyrazole derivatives and the use of thesecompounds for the treatment of various diseases and conditions.

BACKGROUND OF THE INVENTION

Glutamate is one of the major excitatory neurotransmitters that iswidely spread in the brain. First indication of its role as anexcitatory messenger was in the 1950's when it was observed thatintravenous administration of glutamate induces convulsions. However,the detection of the whole glutamatergic neurotransmitter system withits various receptors did not take place before the 1970's and 1980'swhen numerous antagonists were developed or, as in the case of PCP andketamine, were identified as antagonists. Finally, in the 1990'smolecular biology provided the tools for the classification of theglutamatergic receptors.

Glutamate is a main excitatory neurotransmitter in the mammalian centralnervous system and N-methyl-D-aspartate (NMDA) receptors are a subtypeof ionotropic glutamate receptors that mediate excitatory synaptictransmission in the brain. NMDA receptors are ubiquitously distributedthroughout the brain and play a key role in synaptic plasticity,synaptogenesis, excitotoxicity, memory acquisition and learning. NMDAreceptors are distinct from other major subtypes of ionotropic glutamatereceptors (AMPA and kainate receptors) in that they are blocked by Mg²⁺at resting membrane potentials, are highly Ca²⁺ permeable, and requireco-activation by two distinct neurotransmitters: glutamate and glycine(or D-serine) (Traynelis S F et al., Pharmacol Rev. 2010; 62(3):405-96).The influx of Ca²⁺ through NMDA receptors triggers signaling cascadesand regulates gene expression that is critical for different forms ofsynaptic plasticity including both long-term potentiation of synapseefficacy (LTP) (Berberich S et al., Neuropharmacology 2007; 52(1):77-86)and long-term depression (LTD) (Massey, P V et al., J Neurosci. 2004 8;24(36):7821-8).

The vast majority of the mammalian NMDA receptors form a heterotetramermade of two obligatory GluN1 units and two variable GluN2 receptorsubunits encoded by the GRIN1 gene and one of four GRIN2 genes,respectively. One or both GluN2 subunits can be potentially replaced bya GluN3A or a GluN3B subunit. The GRIN1 gene product has 8 splicevariants while there are 4 different GRIN2 genes (GRIN2A-D) encodingfour distinct GluN2 subunits. The glycine binding site is present on theGluN1 subunit and the glutamate binding site is present on the GluN2subunit.

The GluNR2 subunits play a dominant role in determining the functionaland pharmacological properties of the NMDA receptor assembly and exhibitdistinct distribution in different areas of the brain. For instance,GluN2B subunits are expressed primarily in the forebrain in the adultmammalian brain (Paoletti P et al., Nat Rev Neurosci. 2013;14(6):383-400; Watanabe M et al., J Comp Neurol. 1993; 338(3):377-90)and are implicated in learning, memory processing, mood, attention,emotion and pain perception (Cull-Candy S et al., Curr Opin Neurbiol.2001; 11(3):327-35).

Compounds that modulate GluN2B-containing NMDA receptor function can beuseful in treatment of many neurological and psychiatric disordersincluding but not limited to bipolar disorder, major depressive disorder(Miller O H et al., eLife. 2014; 3:e03581; Li N et al., Biol Psychiatry2011; 69(8):754-61), treatment-resistant depression (Preskorn S H et al.J Clin Psychopharmacol. 2008; 28(6):631-7) and other mood disorders(e.g., postpartum depression, seasonal affective disorder and the like),Alzheimer's disease (Hanson J E et al., Neurobiol Dis. 2015; 74:254-62;Li S et al., J Neurosci. 2011; 31(18):6627-38), Parkinson's disease(Duty S, CNS Drugs. 2012; 26(12):1017-32; Steece-Collier K et al., ExpNeurol. 2000; 163(1):239-43; Leaver K R et al. Clin Exp PharmacolPhysiol. 2008; 35(11):1388-94), Huntington's chorea (Tang T S et al.,Proc Natl Acad Sci USA. 2005; 102(7):2602-7; Li L et al., J Neurphysiol.2004; 92(5):2738-46), multiple sclerosis (Grasselli G et al., Br JPharmacol. 2013; 168(2):502-17; Farjam M et al., Iran J Pharm Res. 2014;13(2):695-705), cognitive impairment (Wang D et al. 2014, Expert OpinTher Targets Expert Opin Ther Targets. 2014; 18(10):1121-30), headinjury (Bullock M R et al., Ann N Y Acad Sci. 1999; 890:51-8), spinalcord injury, stroke (Yang Y et al., J Neurosurg. 2003; 98(2):397-403),epilepsy (Naspolini A P et al., Epilepsy Res. 2012 June; 100(1-2):12-9),movement disorders (e.g. dyskinesias) (Morissette M et al., Mov Disord2006; 21(1):9-17), various neurodegenerative diseases (e.g. amyotrophiclateral sclerosis (Fuller P I et al., Neurosci Lett. 2006;399(1-2):157-61) or neurodegeneration associated with bacterial orchronic infections), pain (e.g. chronic, cancer, post-operative andneuropathic pain (Wu L J and Zhuo M, Neurotherapeutics. 2009;6(4):693-702), diabetic neuropathy, migraine (Peeters M et al., JPharmacol Exp Ther. 2007; 321(2):564-72), cerebral ischemia (Yuan H etal., Neuron. 2015; 85(6):1305-18), schizophrenia (Grimwood S et al.,Neuroreport. 1999; 10(3):461-5), encephalitis (Dalmau J. et al. LancetNeurol. 2008; 7(12):1091-8), autism and autism spectrum disorders (WonH. et al., Nature. 2012; 486(7402):261-5), memory and learning disorders(Tang, Y. P. et al., Nature. 1999; 401(6748):63-9), obsessive compulsivedisorder (Arnold P D et al., Psychiatry Res. 2009; 172(2):136-9),attention deficit hyperactivity disorder (ADHD) (Dorval K M et al.,Genes Brain Behav. 2007; 6(5):444-52), and addictive illnesses (e.g.alcohol addiction, drug addiction) (Nagy J, 2004, Curr Drug Targets CNSNeurol Disord 2004; 3(3):169-79; Shen H et al., Proc Natl Acad Sci USA.2011; 108(48):19407-12).

SUMMARY OF THE INVENTION

Provided herein are compounds which inhibit the NR2B receptor.

In one aspect, provided herein are compounds, and pharmaceuticallyacceptable salt, solvate, polymorph, or N-oxide of Formula (I):

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, polymorph, orN-oxide thereof for use in medicine, and optionally a pharmaceuticallyacceptable carrier. The pharmaceutical composition may be used in humanor veterinary medicine.

The present invention further provides a method of treating disordersassociated with NMDA hyperactivity, most preferably with NR2Bhyperactivity, the method comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof.

The present invention also provides a method of treating a centralnervous system disorder in a patient in need thereof comprising,administering to said patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound for use in any of themethods described herein. The present invention further provides use ofa compound for the preparation of a medicament for use in any of themethods described herein.

The details of one or more embodiments of the invention are set forth inthe accompanying description below. Other features, objects, andadvantages of the invention will be apparent from the description andfrom the claims.

DETAILED DESCRIPTION

Exemplary Compounds and Compositions

The present invention provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof; wherein:n=1 or 2,Het is selected from:

-   -   R¹ and R² are each independently selected from hydrogen; a        halogen selected from F, Cl, Br; C₁₋₆alkyl, straight or        branched, optionally substituted with at least one substituent,        e.g. 1, 2 or 3 substituents selected from hydroxy, halogen, C₁₋₃        alkoxy optionally substituted with at least one halogen atom,        e.g. with 1, 2 or 3 halogen atoms, and C₃₋₆ cycloalkyl        optionally substituted with at least one halogen atom, e.g. with        1, 2 or 3 halogen atoms; C₃₋₆ cycloalkyl, optionally substituted        with at least one substituent, e.g. 1, 2 or 3 substituents,        selected from hydroxy, halogen, C₁₋₃ alkyl optionally        substituted with at least one halogen atom, e.g. 1, 2 or 3        halogen atoms, and C₁₋₃ alkoxy optionally substituted with at        least one halogen atom, e.g. with 1, 2 or 3 halogen atoms; C₁₋₆        alkoxy, optionally substituted with at least one substituent,        e.g. 1, 2 or 3 substituents selected from hydroxy, halogen, C₁₋₃        alkoxy optionally substituted with at least one halogen atom,        e.g. with 1, 2 or 3 halogen atoms, and C₃₋₆ cycloalkyl        optionally substituted with at least one halogen atom, e.g. with        1, 2 or 3 halogen atoms; —O—C₃₋₆ cycloalkyl, optionally        substituted with at least one substituent, e.g. 1, 2 or 3        substituents, selected from hydroxy, halogen, C₁₋₃ alkyl        optionally substituted with at least one halogen atom, e.g. 1, 2        or 3 halogen atoms and C₁₋₃ alkoxy optionally substituted with        at least one halogen atom, e.g. with 1, 2 or 3 halogen atoms;        —S—C₁₋₃ alkyl, optionally substituted with at least one halogen        atom, e.g. with 1, 2 or 3 halogen atoms; and —SO₂—C₁₋₃ alkyl,        optionally substituted with at least one halogen atom, e.g. with        1, 2 or 3 halogen atoms; and —SF₅; or    -   R¹ and R² together form a 5 to 7 member carbocycle, optionally        substituted with at least one substituent, e.g. 1, 2, 3, 4 or 5        substituents selected from hydroxy, halogen, C₁₋₃ alkyl        optionally substituted with at least one halogen atom, e.g. with        1, 2 or 3 halogen atoms, and C₁₋₃ alkoxy substituted with at        least one halogen atom, e.g. 1, 2 or 3 halogen atoms; or a 5 to        7 member heterocycle containing one to three heteroatoms which        can be O, S or N, optionally substituted with at least one        substituent, e.g. 1, 2, 3, 4 or 5 substituents selected from        hydroxy, halogen, C₁₋₃ alkyl optionally substituted with at        least one halogen atom, e.g. with 1, 2 or 3 halogen atoms, and        C₁₋₃ alkoxy substituted with at least one halogen atom, e.g. 1,        2 or 3 halogen atoms,    -   R³ and R⁴ are each independently selected from hydrogen;        halogen; and C₁₋₅ alkyl, straight or branched, optionally        substituted with at least one halogen atom, e.g. 1, 2 or 3        halogen atoms; provided that at least one of R³ and R⁴        represents hydrogen;    -   R⁵ and R⁶ are each independently selected from hydrogen;        halogen; amino, including C₁₋₆ alkylamino and di(C₁₋₆ alkyl)        amino; C₁₋₅ alkyl, straight or branched, optionally substituted        with at least one substituent, e.g. with 1, 2 or 3 substituents,        selected from halogen, hydroxy, C₁₋₃ alkoxy optionally        substituted with at least one halogen atom, e.g. 1, 2 or 3        halogen atoms, and C₃₋₆ cycloalkyl, optionally substituted with        at least one halogen atom. e.g. 1, 2 or 3 halogen atoms; C₁₋₅        alkoxy, straight or branched, optionally substituted with at        least one substituent, e.g. 1, 2 or 3 substituents, selected        from hydroxy, halogen, C₁₋₃ alkoxy optionally substituted with        at least one halogen atom, e.g. with 1, 2 or 3 halogen atoms,        and C₃₋₆ cycloalkyl optionally substituted with at least one        halogen atom, e.g. with 1, 2 or 3 halogen atoms, and C₃₋₆        cycloalkyl, optionally substituted with at least one        substituent, e.g. 1, 2 or 3 substituents, selected from hydroxy,        halogen, C₁₋₃ alkyl optionally substituted with at least one        halogen atom, e.g. with 1, 2 or 3 halogen atoms, and C₁₋₃ alkoxy        substituted with at least one halogen atom, e.g. 1, 2 or 3        halogen atoms; and    -   R⁷ is selected from hydrogen; C₁₋₅ alkyl, straight or branched,        optionally substituted with at least one substituent, e.g. with        1, 2 or 3 substituents, selected from halogen, hydroxy, C₁₋₃        alkoxy optionally substituted with at least one halogen atom.        e.g. 1, 2 or 3 halogen atoms, and C₃₋₆ cycloalkyl, optionally        substituted with at least one halogen atom, e.g. 1, 2 or 3        halogen atoms; and C₃₋₆ cycloalkyl, optionally substituted with        at least one substituent, e.g. 1, 2 or 3 substituents, selected        from hydroxy, halogen, C₁₋₃ alkyl optionally substituted with at        least one halogen atom, e.g. with 1, 2 or 3 halogen atoms, and        C₁₋₃ alkoxy substituted with at least one halogen atom, e.g. 1,        2 or 3 halogen atoms.

In a specific embodiment, n is 1.

In other embodiments, one of R¹ and R² does not represent hydrogen, orboth of R¹ and R² do not represent hydrogen. When different fromhydrogen, R¹ and R² are preferably located at a meta-position orpara-position of the phenyl ring. For example, the phenyl ring maycontain substituents different from hydrogen at position 3, position 4,positions 3 and 4, or positions 3 and 5, and the substituents at allother positions are hydrogen.

In some specific embodiments, R¹ and R² are each independently selectedfrom F, Cl, Br; C₁₋₄ alkyl, straight or branched, optionally substitutedwith at least one halogen atom, e.g. with 1, 2 or 3 halogen atoms, e.g.methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl,trifluoroethyl; C₃₋₆ cycloalkyl, optionally substituted with at leastone halogen atom, e.g. with 1, 2 or 3 halogen atoms, e.g. cyclopropyl;C₁₋₃ alkoxy, optionally substituted with at least one halogen atom, e.g.with 1, 2 or 3 halogen atoms, e.g. methoxy, difluoromethoxy,trifluoromethoxy; C₁₋₃ alkoxy-C₁₋₃ alkyl, optionally substituted with atleast one halogen atom, e.g. with 1, 2 or 3 halogen atoms, e.g.methoxymethyl; C₃₋₆ cycloalkyl-C₁₋₃ alkyl, optionally substituted withat least one halogen atom, e.g. with 1, 2 or 3 halogen atoms, e.g.cyclopropylmethyl; and C₃₋₆ cycloalkyl-C₁₋₃ alkoxy, optionallysubstituted with at least one halogen atom, e.g. with 1, 2 or 3 halogenatoms, e.g. cyclopropylmethoxy.

In other specific embodiments, R³ and R⁴ are each independently selectedfrom hydrogen; F, Cl, Br; C₁₋₃ alkyl, straight or branched, optionallysubstituted with at least one halogen atom, e.g. with 1, 2 or 3 halogenatoms, e.g. methyl; and provided that at least one of R³ and R⁴ ishydrogen.

In some embodiments, R³ and R⁴ are both hydrogen.

In yet other embodiments, Het is Het is selected from:

wherein R⁵ and R⁶ are each independently selected from hydrogen; F, Cl;amino; C₁₋₃ alkyl, straight or branched, optionally substituted with atleast one substituent, e.g. 1, 2 or 3 substituents selected from halogenatoms, hydroxy, and C₁₋₃ alkoxy, optionally substituted with at leastone halogen atom, e.g. with 1, 2 or 3 halogen atoms, e.g. methyl, ethyl,n-propyl, i-propyl; C₁₋₃ alkoxy, straight or branched, optionallysubstituted with at least one halogen atom, e.g. with 1, 2 or 3 halogenatoms, e.g. methoxy; C₃₋₆ cycloalkyl, optionally substituted with atleast one halogen atom. e.g. with 1, 2 or 3 halogen atoms, e.g.cyclopropyl, cyclobutyl, cyclopentyl; and C₁₋₆ cycloalkyl-C₁₋₃ alkyl,optionally substituted with at least one halogen atom, e.g. with 1, 2 or3 halogen atoms, e.g. cyclopropylmethyl; and

R⁷ is hydrogen; C₁₋₃ alkyl, straight or branched, optionally substitutedwith at least one substituent, e.g. with 1, 2 or 3 substituents,selected from halogen, hydroxy, C₁₋₃ alkoxy optionally substituted withat least one halogen atom, e.g. 1, 2 or 3 halogen atoms, and C₃₋₆cycloalkyl, optionally substituted with at least one halogen atom, e.g.1, 2 or 3 halogen atoms, e.g. methyl, ethyl, n-propyl, i-propyl,cyclopropylmethyl; or C₃₋₆ cycloalkyl, optionally substituted with atleast one substituent, e.g. 1, 2 or 3 substituents, selected fromhydroxy, halogen, C₁₋₃ alkyl optionally substituted with at least onehalogen atom, e.g. with 1, 2 or 3 halogen atoms, and C₁₋₃ alkoxysubstituted with at least one halogen atom, e.g. 1, 2 or 3 halogenatoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl.

In some embodiments, n is 1; R¹ and R² are each independently selectedfrom F, Cl; C₁₋₂ alkyl, optionally substituted with two to three halogenatoms; C₁₋₂ alkoxy, optionally substituted with up to three halogenatoms and Het is

wherein

-   -   R³ and R⁴ are each independently selected from hydrogen, F, and        Cl, provided that at least one of R³ and R⁴ represents hydrogen;    -   R⁵ and R⁶ are each independently selected from hydrogen; amino;        C₁₋₃ alkyl, optionally substituted with at least one halogen        atom, e.g. with 1, 2 or 3 halogen atoms; C₃₋₆ cycloalkyl,        optionally substituted with at least one halogen atom, e.g. with        1, 2 or 3 halogen atoms; and C₃₋₆ cycloalkyl-C₁₋₃ alkyl,        optionally substituted with at least one halogen atom, e.g. with        1, 2 or 3 halogen atoms; and    -   R⁷ is selected from hydrogen; C₁₋₃ alkyl, straight or branched,        optionally substituted with at least one substituent, e.g. with        1, 2 or 3 substituents, selected from halogen, hydroxy, C₁₋₃        alkoxy optionally substituted with at least one halogen atom,        e.g. 1, 2 or 3 halogen atoms, and C₃₋₆ cycloalkyl, optionally        substituted with at least one halogen atom, e.g. 1, 2 or 3        halogen atoms, e.g. methyl, ethyl, n-propyl, i-propyl; and C₃₋₆        cycloalkyl, optionally substituted with at least one        substituent, e.g. 1, 2 or 3 substituents, selected from hydroxy,        halogen, C₁₋₃ alkyl optionally substituted with at least one        halogen atom, e.g. with 1, 2 or 3 halogen atoms, and C₁₋₃ alkoxy        substituted with at least one halogen atom, e.g. 1, 2 or 3        halogen atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl.

Specific non-limiting compounds of the present invention are:

-   4-[2-[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,-   3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-methylpyrazole,-   5-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazole,-   3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-ethylpyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1-ethylpyrazol-4-yl)ethyl]pyrazole,-   3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-(1-ethylpropyl)-pyrazole,-   3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-cyclopentyl-pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,-   3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,-   3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,-   4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,-   4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-[(1    methylpyrazol-4-yl)methyl]pyrazole,-   4-[3-chloro-5-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   1,3-dimethyl-5-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,-   1-methyl-3-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,-   3-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   4-[4-chloro-3-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   4-[2-[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,-   4-[3-chloro-5-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   5-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,-   4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,-   4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole,-   4-[2-[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,-   4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,-   3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-ethyl-pyrazole,-   4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,-   3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,-   3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,-   4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,-   4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,-   4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-yl)methyl)pyrazole,-   4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,-   4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,-   4-[3-(difluoromethyl)-5-fluoro-phenyl]-1-[2-(1H-pyrazol-3-yl)methyl]pyrazole,-   1,3-dimethyl-5-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,-   1-methyl-3-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,-   1-methyl-3-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,-   1,3-dimethyl-5-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,-   5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   4-(4-fluoro-3-methyl-phenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   5-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   3-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   5-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   3-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   4-(3-cyclopropylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   4-(3-methylsulfonylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,-   1-methyl-4-[[4-(3-methylsulfonylphenyl)pyrazol-1-yl]methyl]-pyrazole,-   pentafluoro-[3-[1-(1H-pyrazol-3-ylmethyl)pyrazol-4-yl]]phenyl]-sulfane,-   4-[2-[4-(4-chlorophenyl)-pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,-   5-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   4-(4-chlorophenyl)-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,-   4-(4-chlorophenyl)-1-(1H-pyrazol-3-ylmethyl)pyrazole,-   4-(4-chlorophenyl)-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,-   3-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   5-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   5-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,-   3-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,-   1-methyl-3-[(4-phenylpyrazol-1-yl)methyl]pyrazole,-   1,3-dimethyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole,-   1-methyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole,-   4-[[4-(3-difluoromethoxy-4-chloro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,-   4-[[4-(3-difluoromethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,-   4-[[4-(3-(1,1-difluoroethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,-   3-[[4-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazole,-   3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazole,-   3-[[4-(3-(1,1-difluoroethyl)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazole    as maleate, and-   3-[[4-(3-(difluoromethoxy)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazole    as maleate.

The present invention also provides a pharmaceutical composition atherapeutically effective amount of comprising a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, polymorph, orN-oxide thereof for use in medicine, and optionally a pharmaceuticallyacceptable carrier. The pharmaceutical composition may be used in humanor veterinary medicine.

Certain Definitions

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. In some embodiments, analkyl group is a C₁-C₆ alkyl group. In some embodiments, an alkyl groupis a C₁-C₄ alkyl group. Examples of alkyl groups include methyl (Me)ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl(tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups thatin light of the ordinary skill in the art and the teachings providedherein would be considered equivalent to any one of the foregoingexamples. In some embodiments, alkyl refers to straight or branchedchain hydrocarbon groups. Specific examples in these embodiments aremethyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g.,n-butyl and t-butyl), hexyl and the like.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain and having at least one ofthe hydrogens replaced with a halogen. In some embodiments, a haloalkylgroup is a C₁-C₆ haloalkyl group. In some embodiments, a haloalkyl groupis a C₁-C₄ haloalkyl group. One exemplary substitutent is fluoro.Preferred substituted alkyl groups of the invention includetrihalogenated alkyl groups such as trifluoromethyl groups. Haloalkylincludes and is not limited to CF₃, CH₂F, —CHF₂, —CH₂Cl, —CH₂—CF₃, andthe like. In specific examples, the term (halo)alkyl refers to alkylsubstituted by at least one halogen atom. Examples of these embodimentsinclude fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl.

“Cycloalkyl” refers to monocyclic, non-aromatic hydrocarbon groupshaving from 3 to 7 carbon atoms. Examples of cycloalkyl groups include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and thelike.

The term “cyclic group” includes fully saturated, partially unsaturatedand aromatic carbocyclic or heterocyclic rings, including aromatic(“aryl” or “heteroaryl”) or nonaromatic cyclic groups, for example, 5 to7 membered monocyclic ring systems, which may have at least oneheteroatom in at least one carbon atom-containing ring. A heterocyclicgroup containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selectedfrom nitrogen atoms, oxygen atoms and/or sulfur atoms, where thenitrogen and sulfur heteroatoms may optionally be oxidized and thenitrogen heteroatoms may optionally be quaternized. The heterocyclicgroup may be attached at any heteroatom or carbon atom of the ring orring system. In some embodiments, one or more carbon atoms of theheterocyclic ring are oxidized to form a carbonyl group. The cyclicgroup may be unsubstituted or carry one or more substituents, e.g.halogen, C₁₋₆ (halo)alkyl, C₁₋₆ (halo)alkoxy. OH, etc.

The term “alkoxy” includes a straight chain or branched alkyl group witha terminal oxygen linking the alkyl group to the rest of the molecule.In some embodiments, an alkoxy group is a C₁-C₆ alkoxy group. In someembodiments, an alkoxy group is a C₁-C₄ alkoxy group. Alkoxy includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and soon. In specific embodiments, the term alkoxy, employed alone or incombination with other terms, refers to a group of formula —O-alkyl.Example alkoxy groups in these embodiments include methoxy, ethoxy,propoxy (e.g. n-propoxy and isopropoxy), t-butoxy, hexyloxy and thelike. The term (halo)alkoxy refers to alkoxy substituted by at least onehalogen atom. Examples of (halo)alkoxy groups include fluoromethoxy,difluoromethoxy, and trifluoromethoxy.

The term “heterocycle” represents” a mono- or bi-cyclic hydrocarbon ringstructure optionally containing heteroatoms selected from O, S, and N.Heterocyclyl rings can have 2 to 10 carbon atoms in the ring.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” or “halogen atom” represents chloro, fluoro, bromo, oriodo. In specific embodiments, halo refers to fluorine, chlorine,bromine and iodine, particularly to fluorine, chlorine and bromine, moreparticularly to fluorine and chlorine.

“Benzyl” and —CH₂-phenyl are used interchangeably.

“GluN2B receptors” refers to NMDA receptors containing the GluN2B orNR2B subunit.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans. Inspecific embodiments, “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) may form salts which are also within thescope of this invention. Reference to a compound of the Formula (I)herein is understood to include reference to salts thereof, unlessotherwise indicated. In various embodiments, the term “salt(s)”, asemployed herein, denotes acidic and/or basic salts formed with inorganicand/or organic acids and bases. Zwitterions (internal or inner salts)are included within the term “salt(s)” as used herein (and may beformed, for example, where the compound comprises an acid moiety such asa carboxyl group). Also included herein are quaternary ammonium saltssuch as alkylammonium salts. Salts of the compounds of the Formula (I)may be formed, for example, by reacting the compound with an amount ofacid or base, such as an equivalent amount, in a medium such as one inwhich the salt precipitates or in an aqueous medium followed bylyophilisation.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, aliginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates,lactates, maleates, methanesulfonates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates (such as those formed with sulfuricacid), sulfonates (such as those mentioned herein), tartrates,thiocyanates, toluenesulfonates such as tosylates, undecanoates, and thelike.

Exemplary basic salts (formed, for example, where the compound comprisesan acidic moiety such as a carboxyl group) include ammonium salts,alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines, N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. The basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

In specific embodiments “pharmaceutically acceptable salts” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17^(th) ed., Mack Publishing Company, Easton,Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered. A “pharmaceutically acceptable excipient” refers to asubstance that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to a subject, such as an inertsubstance, added to a pharmacological composition or otherwise used as avehicle, carrier, or diluent to facilitate administration of an agentand that is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

In treatment methods according to the invention, a therapeuticallyeffective amount of a pharmaceutical agent according to the invention isadministered to a subject suffering from or diagnosed as having such adisease, disorder, or condition. A “therapeutically effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic or prophylactic benefit in patients in need of suchtreatment for the designated disease, disorder, or condition. Effectiveamounts or doses of the compounds of the present invention may beascertained by routine methods such as modeling, dose escalation studiesor clinical trials, and by taking into consideration routine factors,e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the compound, the severity and course of thedisease, disorder, or condition, the subject's previous or ongoingtherapy, the subject's health status and response to drugs, and thejudgment of the treating physician. An example of a dose is in the rangeof from about 0.001 to about 200 mg of compound per kg of subject's bodyweight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). Fora 70-kg human, an illustrative range for a suitable dosage amount isfrom about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

“Compounds of the present invention,” “compounds of the invention” andequivalent expressions, are meant to embrace compounds of the Formula(I) as described herein, which expression includes the pharmaceuticallyacceptable salts, polymorphs, N-oxides, and the solvates, e.g.,hydrates, where the context so permits. Similarly, reference tointermediates, whether or not they themselves are claimed, is meant toembrace their salts, and solvates, where the context so permits.

Furthermore, in the case of the compounds of the invention which containan asymmetric carbon atom, the invention relates to the D form, the Lform and D, L mixtures and also, where more than one asymmetric carbonatom is present, to the diastereomeric forms. Those compounds of theinvention which contain asymmetric carbon atoms, and which as a ruleaccrue as racemates, can be separated into the optically active isomersin a known manner, for example using an optically active acid. However,it is also possible to use an optically active starting substance fromthe outset, with a corresponding optically active or diastereomericcompound then being obtained as the end product.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exemplaryprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

Also included are solvates and hydrates of the compounds of Formula (I)and solvates, polymorphs, N-oxides, and hydrates of theirpharmaceutically acceptable salts.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted, unless otherwise indicated.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can be radiolabeled, that is, contain one or morenon-radioactive or radioactive isotopes, such as for example, deuterium(²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will beunderstood that, in a compound where such isotopic substitution is made,the following atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art. Likewise, the invention may include thepreparation of isotopic variants with radioisotopes, in the instance forexample, where the resulting compounds may be used for drug and/orsubstrate tissue distribution studies. Radiolabeled compounds of theinvention can be used in diagnostic methods such as single-photonemission computed tomography (SPECT). The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for their easeof incorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in positron emissiontopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the invention, radioactive ornot, are intended to be encompassed within the scope of the invention.In one aspect, provided herein are deuterated or tritiated analogs ofcompounds of Formula I.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

Compounds of the invention may also exist as “rotamers,” that is,conformational isomers that occur when the rotation leading to differentconformations is hindered, resulting in a rotational energy barrier tobe overcome to convert from one conformational isomer to another.

The compounds of this invention may possess one or more asymmetriccenters, such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

In some embodiments, the compound can be provided as a prodrug. The term“prodrug”, as employed herein, denotes a compound which, uponadministration to a subject, undergoes chemical conversion by metabolicor chemical processes to yield a compound of the Formula (I), or a saltand/or solvate thereof.

In some embodiments, the compounds of the invention, and salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compound of the invention, or saltthereof

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is understoodthat substitution at a given atom is limited by valency.

The compounds according to the invention have been found to havepharmacologically important properties which can be usedtherapeutically. The compounds of the invention can be used alone, incombination with each other or in combination with other activecompounds. Compounds of Formula (I) may be inhibitors of NMDA(N-methyl-D-aspartate)-receptors, more particularly subtype specificinhibitors of NMDA NR2B receptors. It is therefore a part of thesubject-matter of this invention that the compounds of the invention andtheir salts and also pharmaceutical preparations which comprise thesecompounds or their salts, can be used for treating or preventingdisorders associated with, accompanied by and/or covered by NR2Breceptor hyperactivity and/or disorders in which inhibiting NR2Breceptors is of value.

In various embodiments, the compounds of the invention are inhibitors ofthe NR2B receptor with IC₅₀ values <10 μM, preferably ≤1 μM and morepreferably ≤100 nM.

Exemplary Methods of Treatment

The compounds of the invention including their salts, solvates andhydrates, can be used for the treatment of central nervous systemdisorders of mammals including a human.

More particularly, the invention relates to the treatment of neurologicand psychiatric disorders including, but not limited to: (1) mooddisorders or mood (affective) disorders; (2) neurotic, stress-relatedand somatoform disorders including anxiety disorders; (3) disorders ofpsychological development; (4) behavioral syndromes associated withphysiological disturbances and physical factors; (5) extrapyramidal andmovement disorders; (6) episodic and paroxysmal disorders, epilepsy; (7)pain; (8) forms of neurodegeneration; (9) cerebrovascular diseases,acute and chronic; and any sequalae of cerebrovascular diseases.

Examples of mood disorders or mood (affective) disorders that can betreated according to the present invention include, but are not limitedto, bipolar disorder I, such as depressed, hypomanic, manic and mixedform; bipolar disorder II; depressive disorders, such as singledepressive episode or recurrent major depressive disorder, minordepressive disorder, depressive disorder with postpartum onset,depressive disorders with psychotic symptoms; persistent mood disorders,such as cyclothymia, dysthymia, euthymia; and premenstrual dysphoricdisorder.

Examples of disorders belonging to the neurotic, stress-related andsomatoform disorders that can be treated according to the presentinvention include, but are not limited to, anxiety disorders, such asgeneral anxiety disorder, panic disorder with or without agoraphobia,specific phobia, social phobia, chronic anxiety disorders; obsessivecompulsive disorder; reaction to sever stress and adjustment disorders,such as post-traumatic stress disorder (PTSD); other neurotic disorderssuch as depersonalisation-derealisation syndrome.

Examples of disorders of psychological development that can be treatedaccording to the present invention include, but are not limited topervasive developmental disorders, including but not limited toAsperger's syndrome and Rett's syndrome, autistic disorders, childhoodautism and overactive disorder associated with mental retardation andstereotyped movements, specific developmental disorder of motorfunction, specific developmental disorders of scholastic skills.

Examples of behavioral syndromes associated with physiologicaldisturbances and physical factors that can be treated with the presentinvention include, but are not limited to mental and behaviouraldisorders associated with the puerperium, including but not limited topostnatal and postpartum depression; eating disorders, including but notlimited to anorexia nervosa and bulimia nervosa.

Examples of extrapyramidal and movement disorders that can be treatedaccording to the present invention include, but are not limited toParkinson's disease; second Parkinsonism, such as postencephaliticParkinsonism; Parkinsonism comprised in other disorders; Lewis bodydisease; degenerative diseases of the basal ganglia; otherextrapyramidal and movement disorders including but not limited totremor, essential tremor and drug-induced tremor, myoclonus, chorea anddrug-induced chorea, drug-induced tics and tics of organic origin,drug-induced acute dystonia, drug-induced tardive dyskinesia,L-dopa-induced dyskinesia; neuroleptic-induced movement disordersincluding but not limited to neuroleptic malignant syndrome (NMS),neuroleptic induced parkinsonism, neuroleptic-induced early onset oracute dyskinesia, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia, neuroleptic-induced tremor; restless leg syndrome, Stiff-mansyndrome.

Further examples of movement disorders with malfunction and/ordegeneration of basal ganglia that can be treated according to thepresent invention include, but are not limited to dystonia including butnot limited to focal dystonia, multiple-focal or segmental dystonia,torsion dystonia, hemispheric, generalised and tardive dystonia (inducedby psychopharmacological drugs). Focal dystonia include cervicaldystonia (torticolli), blepharospasm (cramp of the eyelid), appendiculardystonia (cramp in the extremities, like the writer's cramp),oromandibular dystonia and spasmodic dysphonia (cramp of the vocalcord).

Examples for episodic and paroxysmal disorders that can be treatedaccording to the present invention include, but are not limited toepilepsy, including localization-related (focal)(partial) idiopathicepilepsy and epileptic syndromes with seizures of localized onset,localization-related (focal)(partial) symptomatic epilepsy and epilepticsyndromes with simple partial seizures, localization-related(focal)(partial) symptomatic epilepsy and epileptic syndromes withcomplex partial seizures, generalized idiopathic epilepsy and epilepticsyndromes including but not limited to myoclonic epilepsy in infancy,neonatal convulsions (familial), childhood absence epilepsy(pyknolepsy), epilepsy with grand mal seizures on awakening, absenceepilepsy, myoclonic epilepsy (impulsive petit mal) and nonspecificatonic, clonic, myoclonic, tonic, tonic-clonic epileptic seizures.

Further examples of epilepsy that can be treated according to thepresent invention include, but are not limited to epilepsy withmyoclonic absences, myoclonic-astatic seizures, infantile spasms,Lennox-Gastaut syndrome, Salaam attacks, symptomatic early myoclonicencephalopathy, West's syndrome, petit and grand mal seizures; statusepilepticus.

Examples of pain include, but are not limited to pain disorders relatedto psychological factors, such as persistent somatoform disorders;acute, chronic and chronic intractable pain, headache; acute and chronicpain related to physiological processes and physical disorders includingbut not limited to back pain, tooth pain, abdominal pain, low back pain,pain in joints; acute and chronic pain that is related to diseases ofthe musculoskeletal system and connective tissue including, but notlimited to rheumatism, myalgia, neuralgia and fibromyalgia; acute andchronic pain that is related to nerve, nerve root and plexus disorders,such as trigeminal pain, postzoster neuralgia, phantom limb syndromewith pain, carpal tunnel syndrome, lesion of sciatic nerve, diabeticmononeuropathy; acute and chronic pain that is related topolyneuropathies and other disorders of the peripheral nervous system,such as hereditary and idiopathic neuropathy, inflammatorypolyneuropathy, polyneuropathy induced by drugs, alcohol or toxicagents, polyneuropathy in neoplastic disease, diabetic polyneuropathy.

Examples of diseases that include forms of neurodegeneration include,but are not limited to, acute neurodegeneration, such as intracranialbrain injuries, such as stroke, diffuse and local brain injuries,epidural, subdural and subarachnoid haemorrhage, and chronicneurodegeneration, such as Alzheimer's disease, Huntington's disease,and ALS.

Examples of cerebrovascular diseases include, but are not limited to,subarachnoid haemorrhage, intracerebral haemorrhage and othernontraumatic intracranial haemorrhage, cerebral infarction, stroke,occlusion and stenosis or precerebral and cerebral arteries, notresulting in cerebral infarction, dissection of cerebral arteries,cerebral aneurysm, cerebral atherosclerosis, progressive vascularleukoencephalopathy, hypertensive encephalopathy, nonpyogenic thrombosisof intracranial venous system, cerebral arteritis, cerebral amyloidangiopathy and sequalae of cerebrovascular diseases.

In some embodiments, administration of a compound of the invention, orpharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof, is effective in preventing the disease; for example, preventinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Exemplary Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of Formula Ior a pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof for use in medicine, e.g. in human or veterinary medicine. Insome embodiments, the composition further comprises a pharmaceuticallyacceptable carrier.

An effective dose of the compounds according to the invention, or theirsalts, solvates or prodrugs thereof is used, in addition tophysiologically acceptable carriers, diluents and/or adjuvants forproducing a pharmaceutical composition. The dose of the active compoundscan vary depending on the route of administration, the age and weight ofthe patient, the nature and severity of the diseases to be treated, andsimilar factors. The daily dose can be given as a single dose, which isto be administered once, or be subdivided into two or more daily doses,and is as a rule 0.001-5000 mg. Particular preference is given toadministering daily doses of 0.1-3000 mg, e.g. 1-2000 mg.

Suitable administration forms are oral, parenteral, intravenous,transdermal, topical, inhalative, intranasal and sublingualpreparations. Particular preference is given to using oral, parenteral,e.g. intravenous or intramuscular, intranasal preparations, e.g. drypowder or sublingual, of the compounds according to the invention. Thecustomary galenic preparation forms, such as tablets, sugar-coatedtablets, capsules, dispersible powders, granulates, aqueous solutions,alcohol-containing aqueous solutions, aqueous or oily suspensions,syrups, juices or drops, can be used.

Solid medicinal forms can comprise inert components and carriersubstances, such as calcium carbonate, calcium phosphate, sodiumphosphate, lactose, starch, mannitol, alginates, gelatine, guar gum,magnesium stearate, aluminium stearate, methyl cellulose, talc, highlydispersed silicic acids, silicone oil, higher molecular weight fattyacids, (such as stearic acid), gelatine, agar agar or vegetable oranimal fats and oils, or solid high molecular weight polymers (such aspolyethylene glycol); preparations which are suitable for oraladministration can comprise additional flavourings and/or sweeteningagents, if desired.

Liquid medicinal forms can be sterilized and/or, where appropriate,comprise auxiliary substances, such as preservatives, stabilizers,wetting agents, penetrating agents, emulsifiers, spreading agents,solubilizers, salts, sugars or sugar alcohols for regulating the osmoticpressure or for buffering, and/or viscosity regulators.

Examples of such additives are tartrate and citrate buffers, ethanol andsequestering agents (such as ethylenediaminetetraacetic acid and itsnon-toxic salts). High molecular weight polymers, such as liquidpolyethylene oxides, microcrystalline celluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitablefor regulating the viscosity. Examples of solid carrier substances arestarch, lactose, mannitol, methyl cellulose, talc, highly dispersedsilicic acids, high molecular weight fatty acids (such as stearic acid),gelatine, agar agar, calcium phosphate, magnesium stearate, animal andvegetable fats, and solid high molecular weight polymers, such aspolyethylene glycol.

Oily suspensions for parenteral or topical applications can bevegetable, synthetic or semisynthetic oils, such as liquid fatty acidesters having in each case from 8 to 22 carbon atoms in the fatty acidchains, for example palmitic acid, lauric acid, tridecanoic acid,margaric acid, stearic acid, arachidic acid, myristic acid, behenicacid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid,erucic acid or oleic acid, which are esterified with monohydric totrihydric alcohols having from 1 to 6 carbon atoms, such as methanol,ethanol, propanol, butanol, pentanol or their isomers, glycol orglycerol. Examples of such fatty acid esters are commercially availablemiglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate,PEG 6-capric acid, caprylic/capric acid esters of saturated fattyalcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fattyacid esters, such as artificial ducktail gland fat, coconut fatty acidisopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutylphthalate, diisopropyl adipate, polyol fatty acid esters, inter alia.Silicone oils of differing viscosity, or fatty alcohols, such asisotridecyl alcohol, 2-octyl-dodecanol, cetylstearyl alcohol or oleylalcohol, or fatty acids, such as oleic acid, are also suitable. It isfurthermore possible to use vegetable oils, such as castor oil, almondoil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybeanoil.

Suitable solvents, gelatinizing agents and solubilizers are water orwater-miscible solvents. Examples of suitable substances are alcohols,such as ethanol or isopropyl alcohol, benzyl alcohol, 2octyldodecanol,polyethylene glycols, phthalates, adipates, propylene glycol, glycerol,di or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters,morpholines, dioxane, dimethyl sulphoxide, dimethylformamide,tetrahydrofuran, cyclohexanone, etc.

Cellulose ethers which can dissolve or swell both in water or in organicsolvents, such as hydroxypropylmethyl cellulose, methyl cellulose orethyl cellulose, or soluble starches, can be used as film-formingagents.

Mixtures of gelatinizing agents and film-forming agents are alsoperfectly possible. In this case, use is made, in particular, of ionicmacromolecules such as sodium carboxymethyl cellulose, polyacrylic acid,polymethacrylic acid and their salts, sodium amylopectin semiglycolate,alginic acid or propylene glycol alginate as the sodium salt, gumarabic, xanthan gum, guar gum or carrageenan. The following can be usedas additional formulation aids: glycerol, paraffin of differingviscosity, triethanolamine, collagen, allantoin and novantisolic acid.Use of surfactants, emulsifiers or wetting agents, for example of sodiumlauryl sulphate, fatty alcohol ether sulphates,di-Na—N-lauryl-β-iminodipropionate, polyethoxylated castor oil orsorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween),cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylenestearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chlorideor mono/dialkylpolyglycol ether orthophosphoric acid monoethanolaminesalts can also be required for the formulation. Stabilizers, such asmontmorillonites or colloidal silicic acids, for stabilizing emulsionsor preventing the breakdown of active substances such as antioxidants,for example tocopherols or butylhydroxyanisole, or preservatives, suchas phydroxybenzoic acid esters, can likewise be used for preparing thedesired formulations.

Preparations for parenteral administration can be present in separatedose unit forms, such as ampoules or vials. Use is preferably made ofsolutions of the active compound, preferably aqueous solution and, inparticular, isotonic solutions and also suspensions. These injectionforms can be made available as ready-to-use preparations or only beprepared directly before use, by mixing the active compound, for examplethe lyophilisate, where appropriate containing other solid carriersubstances, with the desired solvent or suspending agent.

Intranasal preparations can be present as aqueous or oily solutions oras aqueous or oily suspensions. They can also be present aslyophilisates which are prepared before use using the suitable solventor suspending agent.

Inhalable preparations can present as powders, solutions or suspensions.Preferably, inhalable preparations are in the form of powders, e.g. as amixture of the active ingredient with a suitable formulation aid such aslactose.

The preparations are produced, aliquoted and sealed under the customaryantimicrobial and aseptic conditions.

As indicated above, the compounds of the invention may be administeredas a combination therapy with further active agents, e.g.therapeutically active compounds useful in the treatment of centralnervous system disorders. Exemplary compounds useful in the presentinvention include, but are not limited to:

-   -   Tricyclic antidepressants, e.g. Imipramine, Desipramine,        Clomipramine, Amitriptyline;    -   Tetracyclic antidepressants, e.g. Mianserin;    -   Serotonin/noradrenaline reuptake inhibitors (SNRI), e.g.        Venlafaxine;    -   Selective serotonin reuptake inhibitors (SSRI), e.g. Citalopram,        Fluoxetine, Paroxetine;    -   Selective noradrenaline reuptake inhibitors, e.g. Reboxetine;    -   Monoaminoxidase inhibitors, e.g. Tranylcypromine, Moclobemid;        and    -   other antidepressants, e.g. Oxitriptan, Agomelatine.

For a combination therapy, the active ingredients may be formulated ascompositions containing several active ingredients in a single dose formand/or as kits containing individual active ingredients in separate doseforms. The active ingredients used in combination therapy may beco-administered or administered separately.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration only,it will be understood that the practice of the invention encompasses allof the usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

EXAMPLES

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ACD/Name Version 10.01 (Advanced Chemistry).A prefix of (R/S*) indicates that the compound(s) is/are singleenantiomers; however the stereochemistry shown is arbitrary and theabsolute stereochemistry has not been determined.

Abbreviations

Abbreviations and acronyms used herein include the following:

Acronym Term ACN Acetonitrile aq Aqueous Au(III)Cl₃ Gold(III) chlorideBOP Benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate br. Broad Cs₂CO₃ Cesium carbonate CsF Cesiumfluoride CuI Copper(I) iodide DCE 1,2-dichloroethane DCM Dichloromethanedd Doublet of doublet ddd Doublet of doublet of doublets DIPEAN,N-diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxidedt Doublet of triplets ESI Electrospray ionizationu Et₃N TriethylamineEtOAc Ethyl acetate g Grams HCl Hydrogen chloride H₂O Water HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate HBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateHPLC High-pressure liquid chromatography Hz Hertz J Coupling constantK₃PO₄ Tripotassium phosphate LiCl Lithium chloride LiOH Lithiumhydroxide M Molar m Multiplet m/z Mass to charge ratio MeOH Methanol mgMilligrams MgSO₄ Magnesium sulfate MHz Mega hertz min Minutes mLMilliliter mm Millimeter mmol Millimoles MS Mass spectrometry MsClMethanesulfonyl chloride MTBE Methyl tert-butyl ether N Normal Na₂CO₃Sodium carbonate NaHCO₃ Sodium bicarbonate Na₂SO₄ Sodium sulfate NaHSodium hydride NBS N-bromosuccinimide NCS N-chlorosuccinimide NFBSN-fluorobenzenesulfonimide NH3 Ammonia NMR Nuclear magnetic resonancePd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) Pd(dtbpf)₂Cl₂[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloro- palladium(II)Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloride Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium(0) PPh₃ Triphenylphosphine ppmParts per million q Quadruplet qt Quartet of triplets quint QuintupletRt Retention time rt Room temperature s Singulet SEMCl2-(Trimethylsilyl)ethoxymethyl chloride t Triplet T Temperature tdTriplet of doublets TBAF Tetrabutylammonium fluoride tBuLiTert-butyllithium TFA Trifluoroacetic acid THF Tetrahydrofuran μLMicroliter μm Micrometer x Times NT Not TestedChemistry

Synthesis of Intermediate (1): SEM-pyrazolo-4-boronic Acid Pinacol Ester

SEM-pyrazolo-4-boronic acid pinacol ester was prepared according theprocedure from WO2011/130146, page 84. A solution of pyrazolboronic acidpinacolester (20 g, 103 mmol) in DMF (180 mL) was cooled to 0° C. andtreated with sodium hydride (60% dispersion in oil) (6.2 g, 150 mmol) innitrogen atmosphere.

The reaction mixture was stirred at ambient temperature for 30 minutes.The reaction mixture was then cooled to 0° C. and (2-(chloromethoxyethyl)trimethylsilane (23.65 ml, 134 mmol) was added. The reactionmixture was stirred at ambient temperature overnight.

The reaction mixture was poured into aqueous saturated ammonium chloride(200 mL) containing ice (approximately 200 mL) and stirred until the icemelted. The cold mixture was extracted with ethyl acetate twice. Thecombined organic extracts were washed with water, dried over Na₂SO₄, andconcentrated under reduced pressure to afford SEM-pyrazolo-4-boronicacid pinacol ester (27.6 g, 86% yield).

Synthesis of Intermediate (2): 3-(chloromethyl)-5-propyl-1H-pyrazoleHydrochloride

Step 1

To a suspension of 1.23 g (32 mmol) of LiAlH₄ in THF (100 mL) was addeda solution of 5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.82g, 10 mmol) in THF (50 mL) in small portions at 0° C. After stirring for1 h at 0° C. and 12 h at room temperature, the mixture was hydrolyzedwith a water-methanol solution (v/v, 85:15) (100 mL). The metallichydroxides were filtered off and washed with ethanol.

The organic layer was separated and the aqueous one was extracted withdichloromethane (3×100 mL). These extracts were then combined with theabove organic layer, dried (Na₂SO₄) and evaporated to dryness. Aresidual syrup was obtained and purified by flash chromatography onsilica gel using toluene-acetone-ethanol (v/v, 1:1:1) as the eluent.

Removal of the solvent from the appropriate fractions gave(5-propyl-1H-pyrazol-3-yl)-methanol. Yield: 840 mg (60%).

Step 2

To a mixture of (5-propyl-1H-pyrazol-3-yl)-methanol (840 mg, 6 mmol) indichloromethane (25 mL), neat SOCl₂ (100 mL) was added in portions at 0°C. and stirred at room temperature for 12 h. The excess SOCl₂ wasremoved by distillation under reduced pressure. The residue wasdissolved in ethanol (150 mL) and filtered, and diethylether was addedto produce white plates. Yield: 1.11 g (95%) MS (ESI m/z) 159.0 [M+H]⁺.

Synthesis of Intermediate (3): 3-(chloromethyl)-5-ethyl-1H-pyrazoleHydrochloride

5-Ethyl-1H-pyrazole-3-carboxylic acid ethyl ester was obtained by theprocedure of L. Wang, Chemistry a European Journal, 2013, vol. 19 (23),7555-7560.

Starting from 5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester,intermediate (3), i.e. 3-(chloromethyl)-5-ethyl-1H-pyrazolehydrochloride was obtained analogously to the procedure as described forintermediate (2). MS (ESI m/z) 145.6 [M+H]⁺.

Synthesis of Intermediate (4): 4-(chloromethyl)-3-methyl-1H-pyrazoleHydrochloride

3-Methyl-1H-pyrazole-4-carboxylic acid ethyl ester was obtained by theprocedure of WO2009/137338. N,N-dimethyl-formamide dimethyl acetal andethyl acetoacetate were refluxed for 1 h followed by stirring withhydrazine hydrate in ethanol at 80° C. for 2 h.

Starting from 3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester,intermediate (4), i.e. 4-(chloromethyl)-3-methyl-1H-pyrazolehydrochloride was obtained analogously to the procedure as described forintermediate (2). MS (ESI m/z) 130.5 [M+H]⁺.

Synthesis of Intermediate (5): 4-(chloromethyl)-3-ethyl-1H-pyrazoleHydrochloride

3-Ethyl-1H-pyrazole-4-carboxylic acid ethyl ester was obtainedanalogously to the procedure as described for intermediate (4).

N,N-dimethyl-formamide dimethyl acetal and 3-oxo-pentanoic acid ethylester were refluxed for 1 h followed by stirring with hydrazine hydratein ethanol at 80° C. for 2 hours.

Starting from 3-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester,intermediate (5), i.e. 4-(chloromethyl)-3-ethyl-1H-pyrazolehydrochloride was obtained analogously to the procedure as described forintermediate (2). MS (ESI m/z) 144.6 [M+H]⁺.

Synthesis of Intermediate (6): 3,5-bis(chloromethyl)-1H-pyrazoleHydrochloride

Intermediate (6) was synthesized according to T. G. Schenk et al, Inorg.Chem. 1985, 24, 2334-2337.

Commercially available intermediates useful in the present inventioninclude:

-   5-(chloromethyl)-3-methyl-1H-pyrazole hydrochloride, available from    VitasMLab, order ID: BBL019538-   5-(chloromethyl)-1,3-dimethyl-1H-pyrazole, available from ABCR,    order ID: AB 224372-   3-(chloromethyl)-1-methyl-1H-pyrazole, available from ABCR, order    ID: AB 200747-   4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride, available from    Aldrich, order ID: CBR01696-1G-   4-(2-chloroethyl)-1H-pyrazole hydrochloride, available from ABCR,    order ID: AB 266246-   3-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride, available from    Fluorochem, order ID: 313369-   4-(chloroethyl)-3,5-dimethyl-1H-pyrazole, available from ChemDiv,    order ID: BB01-4360-   3-(chloromethyl)-1H-pyrazole hydrochloride, available from ChemDiv,    order ID: BB20-2557-   4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride, available from    ChemDiv, order ID: BB57-1549-   5-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride, available from    ChemDiv, order ID: BB57-3435-   3-(chloromethyl)-1-cyclopentyl-1H-pyrazole, available from Enamine,    order ID: EN300-84084-   3-(chloromethyl)-1-isopropyl-1H-pyrazole, available from Enamine,    order ID: EN300-74576-   3-(chloromethyl)-1-(pentan-3-yl)-1H-pyrazole, available from    Enamine, order ID: EN300-84091-   4-(2-chloroethyl)-1-ethyl-1H-pyrazole, available from Enamine, order    ID: BBV-34543900-   5-(2-chloroethyl)-1-ethyl-1H-pyrazole, available from Enamine, order    ID: BBV-38136817-   4-(2-chloroethyl)-1-methyl-1H-pyrazole, available from Enamine,    order ID: BBV-41178358-   5-(2-chloroethyl)-1-methyl-1H-pyrazole, available from Enamine,    order ID: BBV-38136179-   4-(4-chlorophenyl)-1H-pyrazole, available from Peakdale, UK, order    ID: 1002465-   4-(3,5-difluorophenyl)-1H-pyrazole, available from Peakdale, UK,    order ID: 3002914-   4-(4-bromophenyl)-1H-pyrazole, available from ABCR, order ID: AB    235347-   4-(3-bromophenyl)-1H-pyrazole, available from ABCR, order ID: AB    233743-   4-phenyl-1H-pyrazole, available from Enamine, order ID: EN300-07023

Example 1: Succinate Salt of4-[2-[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole

Step 1: 4-bromo-1-chloro-2-difluoromethoxy-benzene

4-bromo-1-chloro-2-difluoromethoxy-benzene was prepared according to themethod described in WO2007/065655, which is incorporated herein byreference in its entirety.

4-bromo-2-chlorophenol (10.0 g; 48 mmol) was dissolved in DMF (100 mL)and water (15 mL) was added followed by sodium chloro-2,2-difluoroacetate (21.5 g, 150 mmol) and potassium carbonate (13.2 g, 96 mmol).

The mixture was stirred for 15 minutes at room temperature and thenheated to 100° C. for 2 hours under nitrogen. The mixture waspartitioned between water (200 mL) and ethyl acetate (200 mL). Theorganic phase was separated, dried over sodium sulphate, filtered, andconcentrated in vacuum to give a crude product.

The crude product was purified by silica gel chromatography eluting with0-80% EtOAc in hexane to give 4-bromo-1-chloro-2-difluoromethoxy-benzene(7.5 g, 61% yield) as colorless oil.

Step 2: 4-(4-chloro-3-difluoromethoxy-phenyl)-1-SEM-1H-pyrazole

The mixture of 4-bromo-1-chloro-2-difluoromethoxy-benzene (7.5 g, 29mmol), SEM-pyrazolo-4-boronic acid pinacol ester (17.2 g, 53 mmol),Na₂CO₃ (6.4 g, 60 mmol), toluene (300 mL), ethanol (50 mL) and water (25mL) was vacuumed and refilled with nitrogen, followed by the addition ofPd(PPh₃)₄ (1.155 g, 1 mmol).

After stirring at 90° C. for 6 hours the mixture was cooled to roomtemperature and water (200 mL) was added. The organic phase wasseparated, dried over sodium sulphate, filtered, and concentrated invacuum to give a crude product. Purification using column chromatography(5-10% methanol in dichloromethane as eluent) and recrystallization fromethanol provided the product. Yield: 6.08 g (56%).

Step 3: 4-(4-chloro-3-difluoromethoxy-phenyl)-1H-pyrazole

To a solution of 4-(4-chloro-3-difluoromethoxy-phenyl)-1-SEM-1H-pyrazole(5.1 g, 13.6 mmol) in dry dioxane (50 mL) was added hydrogen chloride,4.0 M solution in dioxane (34 mL, 136 mmol). The reaction mixture wasstirred at room temperature for 16 hours, then concentrated in vacuum togive a solid, which was dissolved in EtOAc (200 mL).

An aqueous saturated NaHCO₃ solution was added (200 mL), the layers wereseparated, and the aqueous phase was extracted 3 times with EtOAc (3×100mL). The combined organic phases were dried over sodium sulphate andconcentrated in vacuum to give a solid. This product was then dissolvedCH₂Cl₂ and purified by flash column chromatography on silica gel(elution with CH₂CL₂/MeOH 100/0 to 95/5). The fraction with the productwas concentrated to give a white solid. Yield: 2.6 g (78%). MS (ESI m/z)245.6 [M+H]⁺.

Step 4:4-{2-[4-(4-Chloro-3-difluoromethoxy-phenyl)-pyrazol-1-yl]-ethyl}-3,5-dimethyl-1H-pyrazole

To a solution of 4-(4-chloro-3-difluoromethoxy-phenyl)-1H-pyrazole (123mg, 0.50 mmol) in dry DMF (4.0 mL) was vacuumed and refilled withnitrogen, followed by addition of sodium hydride, 60% in paraffin oil(22 mg, 0.55 mmol).

The reaction mixture was stirred at room temperature for 20 minutes,then 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole (159 mg, 1.0 mmol)(ChemDiv, BB01-4360) was added. The reaction mixture was stirred at roomtemperature for 20 hours. The mixture was partitioned between water (50mL) and ethyl acetate (50 mL).

The organic phase was separated, dried over sodium sulphate, filtered,and concentrated in vacuo to give a crude product. The crude product waspurified by silica gel chromatography eluting with 0-100% EtOAc inhexane to give4-{2-[4-(4-Chloro-3-difluoromethoxy-phenyl)-pyrazol-1-yl]-ethyl}-3,5-dimethyl-1H-pyrazole(123 mg, 67% yield) as colorless resin. MS (ESI m/z) 367.7 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) ∂ 1.98 (s, 6H); 2.82 (t, 2H, J=7.35); 4.12 (t,2H, J=7.35); 7.18 (t, 1H, J=7.34); 7.46 (m, 1H); 7.52 (m, 2H); 7.95 (s,1H); 8.11 (s, 1H); 11.92 (s, 1H).

Step 5 Formation of the Succinate Salt of4-{2-[4-(4-chloro-3-difluoromethoxy-phenyl)-pyrazol-1-yl]-ethyl}-3,5-dimethyl-1H-pyrazole

To a mixture of4-{2-[4-(4-chloro-3-difluoromethoxy-phenyl)-pyrazol-1-yl]-ethyl}-3,5-dimethyl-1H-pyrazole(1.00 g, 2.83 mmol) and succinic acid (1.00 g, 2.83 mmol), was addedethanol (30 mL) and the mixture was heated to 78° C. and stirred for 5minutes until clear solution. The solvent was evaporated and theresulting solid was dried overnight at 50° C. under reduced pressure, toyield example 1 (1.00 g, 2.83 mmol) as a white solid. Succinate salt(.C₄H₆O₄) (m.p.: 79-81° C.)

The examples in Table 1 were prepared as described in example 1replacing 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with theappropriate chloroalkyl-1H-pyrazole derivative.

TABLE 1[4-(4-chloro-3-difluoromethoxy-phenyl)-pyrazol-1-yl]-derivatives.

Example R Name-Structure form MW m.p. ° C. 2

3-[[4-[4-Chloro-3- (difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole base 339.7 88-91

3

5-[[4-[4-Chloro-3- (difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole  

base 353.7 80-84 4

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole base 339.7 106-107

5

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole  

base 339.7 63-66 6

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[(1H-pyrazol-3-ylmethyl)pyrazole base 325.7 110-114

7

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazole base 325.7 170-173

8

3-[[4-[4-Chloro-3- (difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-ethyl-pyrazole base 353.7 65-68

9

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole  

base 339.7 108-111 10

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[2-(1-ethylpyrazol-4-yl)ethyl]pyrazole  

succinate 366.7 63-67 11

3-[[4-[4-Chloro-3- (difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-(1-ethylpropyl)pyrazole  

succinate 394.8 resin 12

3-[[4-[4-Chloro-3- (difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-cyclopentyl-pyrazole  

succinate 392.8 resin 13

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole  

base 339.7 107-110 14

3-[[4-[4-Chloro-3- (difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole  

base 353.7 103-104 15

3-[[4-[4-Chloro-3- (difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole  

citrate 367.4 resin 16

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole  

base 339.7 134-136 17

4-[4-Chloro-3- (difluoromethoxy)phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole  

citrate 352.4 resin

Example 18:4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole

The compound of example 18 was prepared as described in example 1replacing 5-bromo-2-chloro-phenol with 5-bromo-2-fluoro-phenol andreplacing 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 78-81° C.; MS (ESI m/z) 309.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂3.31 (s, 2H); 7.14 (t, 1H, J=7.27); 7.44 (m, 1H); 7.57 (m, 2H); 8.26 (s,2H); 8.14 (dd, 1H, J=8.01); 12.80 (s, 1H).

Example 19:4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole

The compound of example 19 was prepared as described in example 18replacing 3-chloromethyl-1H-pyrazole with4-chloromethyl-1-methyl-1H-pyrazole. m.p.: 105-110° C.; MS (ESI m/z)323.2 [M+H]⁺.

Example 20:4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazoleTartrate

The compound of example 20 was prepared as described in example 18replacing 3-chloromethyl-1H-pyrazole with4-chloromethyl-5-ethyl-1H-pyrazole hydrochloride.

m.p.: resin; MS (ESI m/z) 337.3 [M+H]⁺.

Example 21:4-[3-chloro-5-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole

The compound of example 21 was prepared as described in example 1replacing 5-bromo-2-chloro-phenol with 5-bromo-3-chloro-phenol andreplacing 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 87-90° C.; MS (ESI m/z) 325.7 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂5.31 (s, 2H); 6.22 (s, 1H); 7.34 (t, 1H, J=7.35); 7.49 (m, 1H); 8.02 (s,1H); 8.36 (s, 1H); 12.81 (s, 1H).

Example 22:1,3-dimethyl-5-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole Succinate

The compound of example 22 was prepared as described in example 1replacing 4-bromo-1-chloro-2-difluoromethoxy-benzene with1-bromo-3-trifluoromethoxy-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 69-73° C. succinate salt, 1:1; MS (ESI m/z) 336.3 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) ∂ 2.51 (s, 3H); 3.31 (s, 3H); 3.75 (s, 2H); 5.40 (s,1H); 6.01 (s, 1H); 7.18 (d, 1H, J=8.46); 7.49 (dd, 1H, J=8.22); 7.62 (d,1H, J=8.22); 8.02 (s, 1H); 8.33 (s, 1H).

Example 23:1-Methyl-3-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazoleSuccinate

The compound of example 23 was prepared as described in example 22replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole. m.p.: 90-95° C., succinate salt,1:1; MS (ESI m/z) 323.2 [M+H]⁺.

Example 24:3-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole

The compound of example 24 was prepared according to following reactionscheme:

Step 1: 4-bromo-1-chloro-2-difluoromethyl-benzene

To a solution of 5-bromo-2-chloro-benzaldehyde (4.4 g, 20 mmol) indichloromethane (DCM) (50 mL) was added DAST (diethylaminosulfurtrifluoride) (4.03 g, 25 mmol) and the mixture was stirred at roomtemperature for 18 hours under nitrogen atmosphere. The reaction mixturewas quenched into ice-water and extracted with DCM. The organic layerwas dried and concentrated. Yield: 3.1 g (64%).

The compound of example 24 was prepared as described in example 1replacing 4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-1-chloro-2-difluoromethyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole. m.p.: 84-88° C.; MS (ESI m/z) 323.7[M+H]⁺.

The examples in Table 2 were prepared as described in example 24replacing 3-chloromethyl-1-methyl-1H-pyrazole with the appropriatechloroalkyl-1H-pyrazole derivative.

TABLE 2 [4-(4-chloro-3-difluoromethyl-phenyl)-pyrazol-1-yl]-derivatives

Example R Name-Structure form MW m.p. ° C. 25

5-[[4-[4-Chloro-3- (difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole  

base 337.7 85-87 26

4-[4-Chloro-3- (difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole base 309.7 102-106

27

4-[2-[4-[4-Chloro-3- (difluoromethyl)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole  

HCl 351.8 49-53

Example 28:4-[3-chloro-5-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole

The compound of example 28 was prepared as described in example 24replacing 5-bromo-2-chloro-benzaldehyde with5-bromo-3-chloro-benzaldehyde and replacing3-chloromethyl-1-methyl-1H-pyrazole with 3-chloromethyl-1H-pyrazole.m.p.: 104-105° C.; MS (ESI m/z) 309.7 [M+H]⁺.

Example 29:5-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazoleSuccinate

The compound of example 29 was prepared as described in example 1replacing 4-bromo-1-chloro-2-difluoromethoxy-benzene with5-bromo-2-chloro-1-trifluoromethyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 133-136° C. succinate salt, 1:1; MS (ESI m/z) 355.7 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) ∂ 2.51 (s, 3H); 3.32 (s, 3H); 3.76 (s, 2H); 5.41 (s,1H); 6.10 (s, 1H); 7.69 (d, 1H, J=8.17); 7.20 (dd, 1H, J=8.50); 8.01 (s,1H); 8.44 (s, 1H).

Example 30:3-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole

The compound of example 30 was prepared as described in example 29replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole. m.p.: 84-88° C.; MS (ESI m/z) 341.7[M+H]⁺.

Example 31:3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 31 was prepared according to following reactionscheme:

Step 1: 4-Bromo-1-fluoro-2-difluoromethyl-benzene

To a solution of 5-bromo-2-fluoro-benzaldehyde (4.0 g, 20 mmol) in DCM(50 mL) was added DAST (diethylaminosulfur trifluoride) (4.03 g, 25mmol) and the mixture was stirred at room temperature for 18 hours undernitrogen atmosphere. The reaction mixture was quenched into ice-waterand extracted with DCM. The organic layer was dried and concentrated.Yield: 2.74 g (61%).

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-1-fluoro-2-difluoromethyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole. m.p.: 100-103° C.; MS (ESI m/z)307.2 [M+H]⁺.

The examples in Table 3 were prepared as described in example 31replacing 3-chloromethyl-1-methyl-1H-pyrazole with the appropriatechloroalkyl-1H-pyrazole derivative.

TABLE 3 [4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]-derivatives

Example R Name-Structure form MS m.p. ° C. 32

5-[[4-[3-(Difluoromethyl)-4-fluoro- phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole  

base 321.3 44-48 33

4-[3-(Difluoromethyl)-4-fluoro- phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole base 307.2 71-73

34

4-[3-(Difluoromethyl)-4-fluoro- phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole  

base 307.2 90-92 35

4-[3-(Difluoromethyl)-4-fluoro- phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole base 293.2 resin

36

4-[2-[4-[3-(Difluoromethyl)-4-fluoro- phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole  

base 335.3 resin 37

4-[3-(Difluoromethyl)-4-fluoro- phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole  

succinate 307.2 104-106 38

3-[[4-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-ethyl-pyrazole  

succinate 321.3 106-108 39

4-[3-(Difluoromethyl)-4-fluoro- phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole  

base 307.2 113-115 40

3-[[4-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole  

citrate 321.0 resin 41

3-[[4-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole citrate 335.0 140-14242

4-[3-(Difluoromethyl)-4-fluoro- phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole  

citrate 306.9 resin 43

4-[3-(Difluoromethyl)-4-fluoro- phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole  

L(+)- tartrate 321.3 resin

Example 44:4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazoleSuccinate

The compound of example 44 was prepared according to following reactionscheme:

Step 1: 4-bromo-2-(1,1-difluoro-ethyl)-1-fluoro-benzene

To a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone (4.34 g, 20 mmol)in DCM (50 mL) was added DAST (diethylaminosulfur trifluoride) (4.03 g,25 mmol) and the mixture was stirred at room temperature for 18 hoursunder nitrogen atmosphere.

The reaction mixture was quenched into ice-water and extracted with DCM.The organic layer was dried and concentrated. Yield: 2.78 g (58%).

The compound was prepared as described in example 1, replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-2-(1,1-difluoro-ethyl)-1-fluoro-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 96-98° C., succinate salt; MS (ESI m/z) 307.2 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) ∂ 2.03 (t, 3H, J=19.11); 2.50 (s, 2H); 3.31 (s, 2H); 5.30(s, 2H); 6.21 (s, 1H); 7.33 (dd, 1H, J=10.01); 7.70 (m, 1H); 8.27 (s,1H); 8.53 (s, 1H); 12.80 (s, 1H).

Example 45:4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazoleSuccinate

The compound of example 45 was prepared as described in example 44replacing 3-chloromethyl-1H-pyrazole with4-chloromethyl-1-methyl-1H-pyrazole. m.p.: resin, succinate salt, 1:1;MS (ESI m/z) 321.3 [M+H]⁺.

Example 46:4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazoleTartrate

The compound of example 46 was prepared as described in example 44replacing 3-chloromethyl-1H-pyrazole with4-chloromethyl-5-ethyl-1H-pyrazole hydrochloride.

m.p.: resin, L(+)-tartaric salt, 1:1; MS (ESI m/z) 335.3 [M+H]⁺.

Example 47:4-[3-(difluoromethyl)-5-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole Succinate

The compound of example 47 was prepared according to following reactionscheme:

The compound was prepared as described in example 31 replacing5-bromo-2-fluoro-benzaldehyde with 5-bromo-3-fluoro-benzaldehyde andreplacing 3-chloromethyl-1-methyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 126-128° C., succinate salt; MS (ESI m/z) 293.2 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) ∂ 2.42 (s, 2H); 2.50 (s, 2H); 5.32 (s, 2H); 6.22 (t,1H, J=1.99); 7.02 (t, 1H, J=55.86); 7.13 (m, 1H, J=8.75); 7.65 (m, 1H);8.02 (s, 1H); 8.35 (s, 1H); 12.32 (s, 1H).

Example 48:1,3-dimethyl-5-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole

The compound of example 48 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with1-bromo-3-trifluoromethyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 68-71° C.; MS (ESI m/z) 321.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂2.11 (s, 3H); 3.74 (s, 3H); 5.41 (s, 2H); 6.02 (s, 1H); 7.59 (d, 1H,J=8.27); 7.90 (d, 1H, J=8.27); 8.06 (s, 1H); 8.39 (s, 1H).

Example 49:1-methyl-3-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazoleSuccinate

The compound of example 49 was prepared as described in example 48replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 90-94° C., succinate salt; MS (ESI m/z) 307.2 [M+H]⁺.

Example 50:1-methyl-3-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole

The compound of example 50 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with1-bromo-4-trifluoromethyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 73-77° C.; MS (ESI m/z) 307.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂3.32 (s, 3H); 3.81 (s, 2H); 5.27 (s, 1H); 6.18 (s, 1H); 7.63 (m, 1H,J=8.27); 7.67 (d, 1H, J=8.19); 7.79 (d, 1H, 8.19); 7.99 (s, 1H); 8.34(s, 1H).

Example 51:1,3-Dimethyl-5-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-Pyrazole

The compound of example 51 was prepared as described in example 50replacing 3-chloromethyl-1-methyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 110-112° C.; MS (ESI m/z) 321.3 [M+H]⁺.

Example 52:5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole

The compound of example 52 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-2-fluoro-1-methyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 65-67° C.; MS (ESI m/z) 285.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂2.13 (s, 3H); 3.35 (s, 3H); 3.79 (s, 3H); 5.42 (s, 2H); 6.03 (s, 1H);7.28 (dd, 1H, J=8.05); 7.34 (dd, 1H, J=7.82); 7.40 (d, 1H, J=11.30);7.96 (s, 1H); 8.21 (s, 1H).

Example 53:3-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 53 was prepared as described in example 52replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 83-86° C., succinate salt; MS (ESI m/z) 271.3 [M+H]⁺.

Example 54:5-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazoleSuccinate

The compound of example 54 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with5-bromo-2-fluoro-1-methyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 80-82° C., succinate salt. MS (ESI m/z) 285.3 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) ∂ 2.13 (s, 3H); 3.34 (s, 3H); 3.34 (s, 4H), 3.78 (s, 3H);5.42 (s, 2H); 6.04 (s, 1H); 7.14 (dd, 1H, J=9.24); 7.34 (m, 1H); 7.53(d, 1H, J=7.84); 7.92 (s, 1H); 8.00 (s, 1H); 8.18 (s, 1H).

Example 55:3-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 55 was prepared as described in example 54replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: resin, succinate salt; MS (ESI m/z) 271.3 [M+H]⁺.

Example 56:4-(4-fluoro-3-methyl-phenyl)-1-(1H-pyrazol-3-ylmethyl)pyrazole

The compound of example 56 was prepared as described in example 54replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 135-139° C.; MS (ESI m/z) 256.2 [M+H]⁺.

Example 57:5-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazoleSuccinate

The compound of example 57 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with5-bromo-2-chloro-1-methyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 70-74° C., succinate salt; MS (ESI m/z) 301.7 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) ∂ 2.10 (s, 3H); 2.89 (s, 3H); 3.30 (d, 4H), 3.75 (s, 3H);5.39 (s, 2H); 6.01 (s, 1H); 7.38 (d, 1H, J=8.74); 7.41 (d, 1H, J=8.74);7.59 (s, 1H); 7.92 (s, 1H); 7.96 (s, 1H); 8.21 (s, 1H).

Example 58:3-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 58 was prepared as described in example 57replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: resin, succinate salt; MS (ESI m/z) 287.7 [M+H]⁺.

Example 59:3-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole

The compound of example 59 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with5-bromo-2-chloro-1-fluoro-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.\

m.p.: 62-65° C.; MS (ESI m/z) 291.7 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂3.80 (s, 3H); 5.25 (s, 2H); 6.16 (s, 1H); 7.44 (d, 1H, J-=9.17); 7.51(dd, 1H, J=7.80); 7.63 (m, 1H); 7.68 (d, 1H, J=10.60); 7.95 (s, 1H);8.28 (s, 1H).

Example 60:5-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole

The compound of example 60 was prepared as described in example 59replacing 3-chloromethyl-1-methyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 90-92° C.; MS (ESI m/z) 305.7 [M+H]⁺.

Example 61:3-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 61 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-2-chloro-1-fluoro-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 109-112° C., succinate salt, 1:1; MS (ESI m/z) 291.7 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) ∂ 3.30 (d, 4H); 3.81 (s, 3H); 5.24 (s, 2H); 6.14(s, 1H); 7.42 (d, 1H, J=9.12); 7.50 (dd, 1H, J=7.85); 7.61 (m, 1H); 7.66(d, 1H, J=10.64); 7.94 (s, 1H); 8.27 (s, 1H).

Example 62:5-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole

The compound of example 62 was prepared as described in example 62replacing 3-chloromethyl-1-methyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 56-60° C.; MS (ESI m/z) 305.7 [M+H]⁺.

Example 63:3-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole

The compound of example 63 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-1,2-dichloro-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 106-110° C.; MS (ESI m/z) 308.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆)∂ 3.80 (s, 3H); 5.24 (s, 2H); 6.17 (s, 1H); 7.58 (s, 2H); 7.63 (s, 1H);7.89 (m, 1H); 7.98 (s, 1H); 8.31 (s, 1H).

Example 64:5-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole

The compound of example 64 was prepared as described in example 64replacing 3-chloromethyl-1-methyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 56-60° C.; MS (ESI m/z) 322.2 [M+H]⁺.

Example 65:5-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole

The compound of example 65 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-1,3-dichloro-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 60-64° C.; MS (ESI m/z) 322.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂2.13 (s, 3H); 2.85 (s, 3H); 3.31 (d, 4H), 3.71 (s, 3H); 5.38 (s, 2H);6.00 (s, 1H); 7.34 (d, 1H, J=8.79); 7.48 (d, 1H, J=8.76); 7.51 (s, 1H);7.92 (s, 1H); 7.99 (s, 1H); 8.28 (s, 1H).

Example 66:3-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 66 was prepared as described in example 65replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: resin, succinate salt; MS (ESI m/z) 308.1 [M+H]⁺.

Example 67:3-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 67 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with2-bromo-5-fluoro-1-methoxy-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 111-114° C., succinate salt, 1:1; MS (ESI m/z) 287.3 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) ∂ 2.25 (s, 3H); 3.35 (s, 3H); 3.87 (d, 4H); 5.29(s, 2H); 6.17 (s, 1H); 6.81 (dd, 1H, J=8.78); 6.98 (dd, 1H, J=11.09);7.64 (m, 1H); 7.89 (s, 1H); 8.16 (s, 1H); 12.19 (s, 2H).

Example 68:5-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazoleSuccinate

The compound of example 68 was prepared as described in example 67replacing 3-chloromethyl-1-methyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: resin, succinate salt, 1:1; MS (ESI m/z) 301.3 [M+H]⁺.

Example 69: 4-(3-cyclopropylphenyl)-1-(1H-pyrazol-3-ylmethyl)pyrazoleSuccinate

The compound of example 69 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with3-bromo-1-cyclopropyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 122-125° C., succinate salt, 1:1; MS (ESI m/z) 265.3 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) ∂ 0.72 (m, 2H); 0.95 (m, 2H); 2.42 (s, 2H); 2.50(s, 2H); 3.31 (s, 1H); 5.30 (s, 2H); 6.89 (d, 1H, J=2.06); 7.18 (d, 1H,J=7.57); 7.20 (s, 1H); 7.26 (dd, 1H, J=7.50); 7.64 (m, 1H); 7.86 (s,1H); 8.16 (s, 1H); 12.29 (s, 2H).

Example 70: 4-(3-methylsulfonylphenyl)-1-(1H-pyrazol-3-ylmethyl)pyrazoleSuccinate

The compound of example 70 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with1-bromo-3-methanesulfonyl-benzene and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 122-125° C., succinate salt, 1:1; MS (ESI m/z) 303.3 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) ∂ 2.30 (s, 3H); 3.05 (s, 2H); 3.10 (s, 2H); 5.13(s, 2H); 6.02 (s, 1H); 7.41 (m, 1H); 7.52 (d, 1H, J=8.54); 7.71 (d, 1H,J=8.54); 7.82 (m, 1H); 7.89 (s, 1H); 8.17 (s, 1H); 12.55 (s, 1H).

Example 71:1-methyl-4-[[4-(3-methylsulfonylphenyl)pyrazol-1-yl]methyl]pyrazoleSuccinate

The compound of example 71 was prepared as described in example 70replacing 3-chloromethyl-1H-pyrazole with4-chloromethyl-1-methyl-1H-pyrazole.

m.p.: resin, succinate salt, 1:1; MS (ESI m/z) 317.3 [M+H]⁺.

Example 72:1-((1H-pyrazol-3-yl)methyl)-4-(3-(pentafluoro-16-sulfanyl)phenyl)-1H-pyrazoleSuccinate

The compound of example 72 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-bromo-1-chloro-2-difluoromethoxy-benzene with1-bromo-3-pentafluoro-phenyl-sulfane and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 142-145° C., succinate salt, 1:1; MS (ESI m/z) 351.3 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) ∂ 2.42 (s, 2H); 2.51 (s, 2H); 3.31 (s, 2H); 5.32(s, 2H); 6.22 (d, 1H, J=2.24); 7.58 (dd, 1H, J=7.75); 7.64 (m, 1H); 7.87(d, 1H, J=7.75); 8.04 (m, 1H); 8.42 (s, 1H); 12.44 (s, 1H).

Example 73:4-[2-[4-(4-chlorophenyl)pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole

The compound of example 73 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-(4-chloro-3-difluoromethoxy-phenyl)-1H-pyrazole with4-(4-chlorophenyl)-1H-pyrazole.

m.p.: 130-134° C.; MS (ESI m/z) 301.7 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆)∂ 1.94 (s, 3H); 2.50 (s, 3H); 2.80 (t, 2H, J=6.99); 4.12 (t, 2H,J=6.99); 7.39 (d, 2H, J=8.09); 7.55 (d, 2H, J=8.09); 7.90 (s, 1H); 8.01(s, 1H); 11.91 (s, 1H).

The examples in Table 4 were prepared as described in example 73replacing 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with theappropriate chloroalkyl-1H-pyrazole derivative.

TABLE 4 4-[2-[4-(4-chlorophenyl)pyrazol-1-yl]-derivatives

Example R Name-Structure form MW m.p. ° C. 74

5-[[4-(4-Chlorophenyl) pyrazol-1-yl]methyl]-1,3- dimethyl-pyrazole  

base 287.7 85-89 75

3-[[4-(4- Chlorophenyl)pyrazol-1- yl]methyl]-1-methyl-pyrazole base273.7 63-66

76

4-(4-Chlorophenyl)-1-[(2- methylpyrazol-3- yl)methyl]pyrazole  

HCl 273.7 106-110 77

4-(4-Chlorophenyl)-1-(1H- pyrazol-3-ylmethyl)pyrazole  

base 259.7 120-124 78

4-(4-Chlorophenyl)-1-[(1- methylpyrazol-4- yl)methyl]pyrazole base 273.7111-112

Example 79: 3-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole

The compound of example 79 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with4-(4-bromophenyl)-1H-pyrazole and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1H-pyrazole.

m.p.: 104-106° C.; MS (ESI m/z) 318.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆)∂

Example 80:5-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole

The compound of example 80 was prepared as described in example 79replacing 3-chloromethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 91-96° C.; MS (ESI m/z) 332.2 [M+H]⁺.

Example 81:5-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazoleSuccinate

The compound of example 81 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with4-(3-bromophenyl)-1H-pyrazole and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 97-99° C., succinic salt, 1:1; MS (ESI m/z) 332.2 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) ∂

Example 82: 3-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazoleSuccinate

The compound of example 82 was prepared as described in example 81replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 116-118° C. succinic salt, 1:1; MS (ESI m/z) 318.1 [M+H]⁺.

Example 83:5-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole

The compound of example 83 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with4-(3,5-difluorophenyl)-1H-pyrazole and replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-chloromethyl-1,3-dimethyl-1H-pyrazole.

m.p.: 90-93° C.; MS (ESI m/z) 289.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) ∂

Example 84:3-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole

The compound of example 84 was prepared as described in example 83replacing 5-chloromethyl-1,3-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 96-100° C.; MS (ESI m/z) 275.2 [M+H]⁺.

Example 85: 1-methyl-3-[(4-phenylpyrazol-1-yl)methyl]pyrazole

The compound of example 85 was prepared according to following reactionscheme:

The compound was prepared as described in example 1 replacing4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with 4-phenyl-1H-pyrazoleand replacing 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with3-chloromethyl-1-methyl-1H-pyrazole.

m.p.: 91-95° C.; MS (ESI m/z) 239.2 [M+H]⁺.

The examples in Table 5 were prepared as described in example 85replacing 3-chloromethyl-1-methyl-1H-pyrazole with the appropriatechloroalkyl-1H-pyrazole derivative.

TABLE 5 4-phenylpyrazol-1-yl-derivatives

Example R Name-Structure form MW m.p. ° C. 86

1,3-Dimethyl-5-[(4- phenylpyrazol-1- yl)methyl]pyrazole  

base 253.3 82-84 87

1-Methyl-5-[(4- phenylpyrazol-1- yl)methyl]pyrazole; succinic acid  

succinate 239.2 85-87

Example 88:4-[[4-(3-difluoromethoxy-4-chloro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole

The compound of example 88 was prepared as described in example 1replacing 4-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole with4-(2-chloromethyl)-3,5-dimethyl-1H-pyrazole in step 4. MS[M+H]⁺=353.8;melting range: 146-148° C.

Example 89:4-[[4-(3-difluoromethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole

The compound of example 89 was prepared as described in example 31replacing 3-chloromethyl-1-methyl-1H-pyrazole with4-(2-chloromethyl)-3,5-dimethyl-1H-pyrazole in step 4. MS[M+H]⁺=321.3;melting range: 154-155° C.

Example 90:4-[[4-(3-(1,1-difluoroethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole

The compound of example 90 was prepared as described in example 45replacing 4-chloromethyl-1-methyl-1H-pyrazole with4-(2-chloromethyl)-3,5-dimethyl-1H-pyrazole in step 4. MS[M+H]⁺=335.3;melting range: 118-120° C.

Example 91:3-[[4-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazoleSuccinate

The compound of example 91 was prepared as described in example 20replacing 4-chloromethyl-5-ethyl-1H-pyrazole with3-chloromethyl-4-ethyl-1H-pyrazole in step 4. MS[M+H]⁺=337.3.

Example 92:3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazole

The compound of example 92 was prepared as described in example 31replacing 3-chloromethyl-1-methyl-1H-pyrazole with3-chloromethyl-4-ethyl-1H-pyrazole in step 4. MS[M+H]⁺=321.3.

Example 93:3-[[4-(3-(1,1-difluoroethyl)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazoleMaleate

The compound of example 93 was prepared as described in example 6replacing 4-bromo-1-chloro-2-difluoromethoxy-benzene with3-bromo-1-(1,1-difluoroethyl)-benzene in step 1.

MS[M+H]⁺=289.4.

Example 94:3-[[4-(3-(difluoromethoxy)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazoleMaleate

The compound of example 94 was prepared as described in example 6replacing 4-bromo-1-chloro-2-difluoromethoxy-benzene with3-bromo-1-difluoromethoxy-benzene in step 1.

MS[M+H]⁺=291.3.

Example 95:4-(4-chloro-3-(difluoromethyl)phenyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-pyrazole

The compound of example 95 was prepared as described in example 24replacing 5-(chloromethyl)-1-methyl-1H-pyrazole with5-(chloromethyl)-1-ethyl-1H-imidazole.

Example 96:4-(4-fluoro-3-methylphenyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-pyrazole

The compound of example 96 was prepared using the methods describedherein.

Example 98:4-(4-chlorophenyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-pyrazole

The compound of example 98 was prepared as described in example 73replacing 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with5-(chloromethyl)-1-ethyl-1H-imidazole.

Example 100: 4-(3,4-dichlorophenyl)-2′-methyl-2′H-1,3′-bipyrazole

4-(3,4-dichlorophenyl)-1H-pyrazole was prepared as described in Example1 Steps 1-3, replacing 4-bromo-1-chloro-2-difluoromethoxy-benzene with4-bromo-1,2-dichloro-benzene in Step 1.

Step 4: 4-(3,4-dichlorophenyl)-2′-methyl-2′H-1,3′-bipyrazole

Copper (II) Acetate (110 mg, 0.6 mmol), pyridine (0.08 mL, 1 mmol),1-methyl-1H-pyrazole-5-boronic acide pinacol ester and4-(3,4-dichlorophenyl)-1H-pyrazole (383 mg, 1.8 mmol) were combined inDMF and stirred for 20 h at 95 degrees C. Extractions were carried outusing water and ethyl acetate and the crude product was purified byflash chromatography using DCM/MeOH (95:5).

Example 101: 4-(3-chloro-4-fluorophenyl)-2′-methyl-2′H-1,3′-bipyrazole

The compound in example 101 was prepared as described for example 100,replacing 4-bromo-1,2-dichloro-benzene with4-bromo-2-chloro-1-fluorobenzene in Step 1.

Example 102:2-((4-(4-chlorophenyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine

The compound of example 102 was prepared as described in example 73replacing 4-(2-chloro-ethyl)-3,5-dimethyl-1H-pyrazole with2-(chloromethyl)imidazo[1,2-a].

Example 103:3-(3-(difluoromethyl)-4-fluorophenyl)-1-((5-((4-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazol-1-yl)methyl)-1H-pyrazol-3-yl)methyl)-1H-pyrazole

Example 104:2-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)pyridineSuccinate

Example 105:2-(1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)pyridineSuccinate

Examples 106-111 were prepared according to the methods described hereinwith the appropriate starting materials.

Example Structure 106 1-((1H-pyrazol-3-yl)methyl-4- (3-chloro-5-(difluoromethoxy)phenyl)-1H- pyrazole succinate

107 4-(2-(4-(4-chlorophenyl)-1H- pyrazol-1-yl)ethyl)-3,5-dimethyl-1H-pyrazole succinate

108 4-(2-(4-(4-chloro-3- (difluoromethoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-3,5- dimethyl-1H-pyrazole succinate

109 5-((4-(3-fluoro-4- methylphenyl)-1H-pyrazol-1-yl)methyl)-1,3-dimethyl-1H- pyrazole

110 4-(3,4-dichlorophenyl)-2′- methyl-2′H-1,3′-bipyrazole

111 4-(3-chloro-4-fluorophenyl)-2′- methyl-2′H-1,3′-bipyrazole

Biological AssaysInhibition of Specific Binding to the Rat NR1/NR2B Receptor

Male Wistar rats (180 to 200 g) were killed by suffocation in a CO₂chamber for two minutes. Whole brains without cerebellum were removedand dissected on ice, placed into closed vials and stored at −70° C.

Membrane fractions were prepared and tested using standard techniques.At the time of the assay, 1 g of the brains was placed into 25 ml of 50mM Tris/10 mM EDTA buffer, pH 7.1, (25 vol. per g of original tissue)and homogenized for 30 sec at 20000 rpm with an Ultraturrax T25 (Jahnke& Kunkel, IKA-Labortechnik, Staufen, Germany). The homogenate wascentrifuged at 4° C. for 10 min at 48000 g (OPTIMA L-70, Beckman, PaloAlto, Calif. 94304, USA).

The supernatant was discarded and the pellet was homogenized on ice for30 sec at 20000 rpm with an Ultraturrax and again centrifuged at 48000 gfor 30 minutes at 4° C. The resultant pellet was resuspended in 25 ml of50 mM Tris/10 mM EDTA buffer, homogenized for 30 sec with anUltraturrax, aliquoted, frozen at −70° C. and stored until use.

After thawing on the day of the assay, a 5 ml membrane aliquot wascentrifuged at 48000 g for 30 min at 4° C. The pellet was resuspended in5 ml of 5 mM Tris/1 mM EDTA buffer, pH 7.4, homogenized for 30 sec at20000 rpm with an Ultraturrax and centrifuged at 48000 g for 30 min at4° C. This was repeated twice. The final pellet was homogenized in 5 mlof 5 mM Tris/1 mM EDTA buffer at 4° C. with an Ultraturrax and used forthe Ifenprodil-binding assay as described in the following.

The incubation mixture of 200 μl contained 5 nmol/l [³H]-Ifenprodil, anoptimised amount of membrane preparation, 5 mM Tris/1 mM EDTA (pH 7.4,100 μM R(+)-3-PPP, 1 μM GBR-12909, 1 μM GBR-12935) and test compound in1% DMSO. Nonspecific binding was estimated in the presence of 10MCP101.606. The samples were incubated for 60 min. at 4° C.

The incubation was terminated by filtration of the membrane preparationsusing Filtermat B (Pharmacia, Uppsala Sweden) and a Micro Cell Harvester(Skatron, Lier, Norway). The Filtermat B had been presoaked with 1%polyethylene imine and carefully washed with 50 mM Tris/HCl-buffer pH7.7 after the filtration to separate free and bound radioactivity. Thefilters were counted in a scintillation counter (Betaplate 1205,Berthold, Wildbad, Germany) in order to determine the specific bindingof [³H]-Ifenprodil.

The optimal amount of membrane preparation in the assay was determinedand optimized for each membrane preparation separately before the test.

Test compounds were either screened at 6 to 10 increasing concentrationsfor the determination of IC₅₀ and Ki or at 2-4 concentrations for thedetermination of the percent inhibition. For pipetting of the incubationmixture the robot Biomek2000 (Fa. Beckman) was used.

For determination of IC₅₀ values the Hill-plot, 2-parameter-model wasused. In the NR1/NR2B binding assay a dissociation constant (K_(D)) of[³H]-Ifenprodil of 9 nM was determined.

NR2B Inhibition, IC₅₀ values NR2B binding assay IC50 % INH % INH Example[nM] @ 1 μM @ 10 μM 1 65.5 NT NT 2 78.4 NT NT 3 146 NT NT 4 119 NT NT 5148 NT NT 6 5.21 NT NT 7 8.23 NT NT 8 281 NT NT 9 152 NT NT 10 250 NT NT11 NT  2.7 NT 12 280 NT NT 13 22.1 NT NT 14 76.2 NT NT 15 163 NT NT 1641.1 NT NT 17 56.0 NT NT 18 8.01 NT NT 19 202 NT NT 20 22.2 NT NT 211021 NT NT 22 2760 NT NT 23 1590 NT NT 24 410 NT NT 25 980 NT NT 26 30.1NT NT 27 7170 NT NT 28 638 NT NT 29 2540 NT NT 30 1010 NT NT 31 264 NTNT 32 323 NT NT 33 371 NT NT 34 866 NT NT 35 17.6 NT NT 36 424 NT NT 372060 NT NT 38 443 NT NT 39 102 NT NT 40 47.0 NT NT 41 114 NT NT 42 202NT NT 43 134 NT NT 44 17.1 NT NT 45 261 NT NT 46 106 NT NT 47 203 NT NT48 1970 NT NT 49 2250 NT NT 50 4250 NT NT 51 9210 NT NT 52 522 NT NT 533840 NT NT 55 871 NT NT 56 78.7 NT NT 57 967 NT NT 58 668 NT NT 59 2190NT NT 60 2170 NT NT 61 1380 NT NT 62 857 NT NT 63 612 NT NT 64 1100 NTNT 65 3810 NT NT 66 5210 NT NT 67 NT 15.1 16.0 68 NT  8.7 26.3 69 831 NTNT 70 2690 NT NT 71 9330 NT NT 72 95.1 NT NT 73 1157 NT NT 74 6060 NT NT75 3040 NT NT 76 7350 NT NT 77 1040 NT NT 78 8280 NT NT 79 4720 NT NT 806210 NT NT 81 4630 NT NT 82 2620 NT NT 83 6020 NT NT 84 NT 14.6 45.7 85NT 22.5 25.3 86 NT  3.8 10.9 87 NT −3.3 28.8 88 152 NT NT 89 736 NT NT90 422 NT NT 91 43.8 NT NT 92 71.2 NT NT 93 25.2 NT NT 94 279 NT NT 9563.5 NT NT 96 77.8 NT NT 98 1060 NT NT 100 3170 NT NT 101 5600 NT NT 102NT 23.3 NT 103 NT 15.5 NT 104 NT 20.9 −0.6 105 NT −1.3  4.4HNR2BC: Effects of Test Articles on Cloned Human NR1/NR2B Ion ChannelsExpressed in Mammalian Cells

The ability of test compounds to act as an antagonist of NR1/NR2B wasevaluated with a calcium influx assay (Calcium 5 Assay Kit, MolecularDevices).

For the antagonist assessment, NR1/NR2B was activated with the positivecontrol agonist (Mg²⁺-free HBPS+100 μM glutamic acid+100 μM glycine).The effect of each test article to inhibit the signal was examined afteragonist stimulation and compared to the positive control antagonist(MK-801). The signal elicited in the presence of the positive agonist(Mg²⁺-free HBPS+100 μM glutamic acid+100 μM glycine) was set to 100 (0%inhibition) and the signal from the positive antagonist (Mg²⁺-freeHBPS+100 μM glutamic acid+100 μM glycine+100 μM MK-801) was set to 0(100% inhibition).

Cell Culture:

A HEK cell line, stable transfected with hNR1/NR2B was used. Thistetracycline inducible cell line is transfected with GRIN1 (GeneBankaccession number NM_007327.2) and GRIN2B (GeneBank accession numberNM_000834.3.). The cells were cultured in cell culture flasks withDMEM/F12 supplemented with 10% FCS, 1% PenStrep and a selection ofadditional antibiotics.

Forty-Eight (48) hours before the assay the cells were plated into96-well black well, flat clear bottom microtiter plates at a density of50000 cells/well. Twenty-Four (24) hours later the receptor expressionwas induced by the addition of 1 μg/ml tetracycline in the presence of 2mM ketamine and 200 μM 7-CKA. After 24 h of receptor induction theplates were used for the assay.

Assay:

The medium was removed and the cells were loaded with 200 μl loadingbuffer (Molecular Devices) in Mg2+-free HBPS containing 100 μM 7-CKA at37° C. for one (1) hour.

The test compounds were then solubilized in 100% DMSO and diluted toyield eight (8) different concentrations in 100% DMSO. A 96 well drugplate was prepared by diluting with water and glycine/glutamate to a5-fold of final test concentration. Fluorescence intensity of the cellsin the plate was measured in a FlexStation using an excitationwavelength of 485 nm and an emission wavelength of 525 nm. Twenty (20)seconds after starting the recordings the compounds together with theagonists glycine (100 μM) and glutamate (100 μM) were added into thewells and the fluorescence measured for ninety (90) seconds in summary.

The IC50 values provided in the paragraph below were determined using a3 parameter plot.

Example IC50 [uM] 2 2.46 4 1.75 6 0.23 7 0.35 14 >10    16 2.15 17 3.7 18 0.37 20  5.97* 26 0.89 31 7.77 35 0.69 39 2.4  40 3.3  41 59.7*  422.3  43 2.66 44 0.53 74 51*   75 33.8*  88 >10    91 1.25 92 11.9* 

Inhibition of Specific Binding to the hERG—Receptor (HERGBD)

A HEK cell line with stable transfected human ERG receptor was used forthe assay. The cells were grown adherently and maintained in DULBECCOS'MEM medium with 10% FBS, 1% non-essential amino acids, 1%Penicillin/Streptomycin and 400 μg/ml G418 (Calbiochem).

Cells were split 2-3 times weekly between 1:3 and 1:4. For bindingassays and membrane preparations the cell culture medium was removed,cells were washed with PBS. Crude membranes for radioligand bindingexperiments were prepared by scraping the cells off the dishes in icecold 20 mM HEPES/0.1 mM KCl/pH 7.2. The cell suspension was homogenizedon ice (Ultra turrax, 3×20 sec.) and the homogenate was spun for 10 min(1° C., 1000 g, OPTIMA, SW28, 2800 U/min). The supernatant was thancentrifuged for 40 min at 100000 g (1° C., OPTIMA, SW28, 23000 U/min).The membrane pellet was re-suspended in 20 mM HEPES/0.1 mM KCl pH 7.2,frozen and stored at −80° C.

After thawing on the day of the assay, the membrane suspension wasdiluted further with 20 mM HEPES/0.1 mM KCl/pH 7.2.

The incubation mixture of 200 μl contained 1.5 nmol/l 3H-Dofetilide,optimized amount of membrane preparation, 20 mM HEPES/0.1 mM KCl/(pH7.2) and inhibitor in 1% DMSO. Nonspecific binding was estimated in thepresence of 10 M Dofetilide. The samples were incubated for 90 min. atRT.

Binding was terminated by filtration of the incubated membranepreparations using Filtermat B (Pharmacia, Uppsala Sweden) and a MicroCell Harvester (Skatron, Lier, Norway). The Filtermat B had beenpresoaked with 1% polyethylen imine and carefully washed with 0.05 MTris/HCl-buffer pH=7.7 after the filtration to separate free and boundradioactivity. The filters were counted in a scintillation counter(Betaplate 1205, Berthold, Wildbad, Germany) in order to determine thespecific binding of [³H]-Dofetilide.

The optimal amount of membrane preparation in the assay was determinedand optimized for each membrane preparation separately in front of usingthe membranes in compound testing.

Test compounds were either screened at 6 to 10 increasing concentrationsfor the determination of IC50 and Ki or at 2-4 concentrations for thedetermination of the percent inhibition. For pipetting of the incubationmixture we routinely use the robot Biomek2000 (Fa. Beckman).

The IC50 values in the table below were determined using the Hill-plot,2-parameter-model.

Example IC50 [uM] 1 12.8 2 8.08 3 23.3 4 52.4 5 64.3 6 9.56 7 52.6 8 419 21.5 10 18.4 11 12.65 12 8.06 13 37 14 16.1 15 7.93 16 64.7 17 35 18135 19 >100 20 22.6 21 33.5 22 22.6 23 9.24 24 4.89 25 49.6 26 4.75 2735.1 28 54.6 29 17.9 30 3.47 31 19.7 32 38.6 33 >100 34 85.8 35 22.6 3629.6 37 38.1 38 >100 39 90.2 40 23.3 41 16 42 71.6 43 57.4 44 >100 4567.8 46 72.9 47 >100 48 37.4 49 19 50 17 51 137 52 >100 54 >100 55 21.156 93.8 57 126 58 12.6 59 7.28 60 31.6 61 24.7 62 41.9 63 10.8 64 14.465 40.4 66 8.86 67 63.3 68 93.6 69 >100 70 >100 71 >100 72 44.7 73 9874 >100 75 131 76 120 77 16.9 78 >100 87 >100 88 43.2 89 88.2 90 84 9148.9 92 27.4 93 129 94 120 95 6.36 96 7.96 98 3.55 100 60.3 101 118 10210.24 103 >10 104 >100RRNR2BB—Inhibition of Specific Binding to the Rat NR1/NR2B Receptor

Male Wistar rats (180 to 200 g) were killed by suffocation in a CO₂chamber for two minutes. Whole brains without cerebellum were removedand dissected on ice, placed into closed vials and stored at −70° C.

Membrane fractions were prepared and tested using standard techniques.At the time of the assay, 1 g of the brains were placed into 25 ml of 50mM Tris/10 mM EDTA buffer, pH=7.1, (25 vol. per g of original tissue)and was homogenized for 30 sec at 20000 U/min with an Ultraturrax T25(Jahnke & Kunkel, IKA-Labortechnik, Staufen, Germany). The homogenatewas centrifuged at 4° C. for 10 min at 48000 g (OPTIMA L-70, Beckman,Palo Alto, Calif. 94304, USA). The supernatant was discarded and thepellet was homogenized on ice for 30 sec at 20000 U/min with anUltraturrax and again centrifuged at 48000 g for 30 minutes at 4° C. Theresulted pellet was resuspended in 25 ml of 50 mM Tris/10 mM EDTAbuffer, homogenized for 30 sec with an Ultraturrax, aliquoted, frozen at−70° C. and stored until use

After thawing on the day of the assay, a 5 ml membrane aliquote wascentrifuged at 48000 g for 30 min at 4° C. The pellet was resuspended in5 ml of 5 mM Tris/1 mM EDTA buffer, pH=7.4, homogenized for 30 sec at20000 U/min with an Ultraturrax and centrifuged at 48000 g for 30 min at4° C. This step was repeated twice. The final pellet was homogenized in5 ml of 5 mM Tris/1 mM EDTA buffer at 4° C. with an Ultraturrax and usedfor the Ifenprodil-binding assay.

The incubation mixture of 200 μl contained 5 nmol/l [³H]-Ifenprodil,optimised amount of membrane preparation, 5 mM Tris/1 mM EDTA (pH 7.4,100 μM R(+)-3-PPP, 1 μM GBR-12909, 1 μM GBR-12935) and inhibitor in 1%DMSO. Nonspecific binding was estimated in the presence of 10 MCP101.606. The samples were incubated for 60 min. at 4° C.

Binding was terminated by filtration of the incubated membranepreparations using Filtermat B (Pharmacia, Uppsala Sweden) and a MicroCell Harvester (Skatron, Lier, Norway). The Filtermat B had beenpresoaked with 1% polyethylen imine and carefully washed with 50 mMTris/HCl-buffer pH=7.7 after the filtration to separate free and boundradioactivity. The filters were counted in a scintillation counter(Betaplate 1205, Berthold, Wildbad, Germany) in order to determine thespecific binding of [³H]-Ifenprodil.

The optimal amount of membrane preparation in the assay has beendetermined and optimised for each membrane preparation separatelyinfront of using the membranes in compound testing.

Test compounds were either screened at 6 to 10 increasing concentrationsfor the determination of IC50 and Ki or at 2-4 concentrations for thedetermination of the percent inhibition. For pipetting of the incubationmixture the robot Biomek2000 (Fa. Beckman) was used.

The IC50 values in the tables below were determined using the Hill-plot,2-parameter-model. In the NR1/NR2B binding assay a dissociation constant(KD) of [³H]-Ifenprodil was determined to be 9 nM. The specific bindingin this assay was about 80%.

Reference compounds and their IC50 values tested in the hERG receptorbinding assay are provided below.

Example IC50 [nM] 1 65.5 2 78.4 3 146 4 119 5 148 6 5.21 7 8.23 8 281 9152 10 250 11 >1000 12 280 13 22.1 14 76.2 15 163 16 41.1 17 56 18 8.00519 202 20 22.2 21 1021 22 2760 23 1590 24 410 25 980 26 30.1 27 7170 28638 29 2540 30 1010 31 264 32 323 33 371 34 866 35 17.6 36 424 37 206038 443 39 102 40 47 41 114 42 202 43 134 44 17.1 45 261 46 106.2 47 20348 1970 49 2250 50 4250 51 9210 52 522 53 3840 54 522 55 871 56 78.7 57967 58 668 59 2190 60 2170 61 1380 62 857 63 612 64 1100 65 3810 66 521067 >10000 68 >10000 69 831 70 2690 71 9330 72 95.1 73 1157 74 6060 753040 76 7350 77 1040 78 8280 79 4720 81 4630 81 6210 82 2620 83 602084 >10000 85 >10000 86 >10000 87 >10000 88 152 89 736 90 422 91 43.8 9271.2 93 25.2 94 279 95 63.5 96 77.8 97 807 98 1060 99 3150 100 3170 1015600 102 >1000 103 >1000 104 >10000 105 >10000Forced Swim Test in Mice

The compounds of the invention show significant antidepressive effectsin the forced swim test in mice, an animal model of depression at dosesof 100 mg/kg or below.

The method, which detects antidepressant activity, follows thatdescribed by Porsolt et al (Arch. Int. Pharmacodyn., 229, 327-336,1977), which is incorporated by reference herein in its entirety.

Mice forced to swim in a situation from which they cannot escape rapidlybecome immobile. Antidepressants decrease the duration of immobility.

Male NMRI mice (Janvier, France), weighing 20-30 g, were individuallyplaced in a cylinder (height=24 cm; diameter=13 cm) containing 10 cmwater (22° C.) from which they cannot escape.

The mice were placed in the water for 6 minutes and the duration ofimmobility during the last 4 minutes was measured. The latency to thefirst bout of immobility was also recorded starting from the beginningof the test. 10 mice were studied per group. The test substance wasadministered p.o. 30 minutes before the test and compared with vehiclecontrol group. The test was performed blind. The results are shown inthe table below.

Minimum effective Example dose (mg/kg p.o.) 2 30 18 10

All patents, patent applications, publications and presentationsreferred to herein are incorporated by reference in their entirety.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

While the foregoing specification teaches the principles of the presentinvention, and specific embodiments of the invention have been describedfor the purposes of illustration, and examples have been provided forthe purposes of illustration, it will be understood that variousmodifications may be made without deviating from the spirit and scope ofthe invention.

The invention claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof; wherein: n is 1 or 2, Het is selected from:

wherein R¹ and R² are each independently selected from hydrogen; ahalogen selected from F, Cl, and Br; C₁₋₆ alkyl, optionally substitutedwith at least one substituent, selected from hydroxy, halogen, C₁₋₃(halo)alkoxy, and C₃₋₆ (halo)cycloalkyl; C₃₋₆ cycloalkyl, optionallysubstituted with at least one substituent, selected from hydroxy,halogen, C₁₋₃ (halo)alkyl and C₁₋₃ (halo)alkoxy; C₁₋₆ alkoxy, optionallysubstituted with at least one substituent, selected from hydroxy,halogen, C₁₋₃ (halo)alkoxy and C₃₋₆ (halo)cycloalkyl; —O—C₃₋₆cycloalkyl, optionally substituted with at least one substituent,selected from hydroxy, halogen, C₁₋₃ (halo)alkyl and C₁₋₃ (halo)alkoxy;—S—C₁₋₃ alkyl, optionally substituted with at least one halogen atom;—SO₂—C₁₋₃ alkyl, optionally substituted with at least one halogen atom;and —SF₅; or R¹ and R² together form a 5 to 7 member carbocycle,optionally substituted with at least one substituent, selected fromhydroxy, halogen, C₁₋₃ (halo)alkyl and C₁₋₃ (halo)alkoxy; and a 5 to 7member heterocycle containing one to three heteroatoms which can be O, Sor N, optionally substituted with at least one substituent, selectedfrom hydroxy, halogen, C₁₋₃ (halo)alkyl and C₁₋₃ (halo)alkoxy; R³ and R⁴are each independently selected from hydrogen; halogen; C₁₋₅(halo)alkyl, optionally substituted with at least one halogen atom,provided that at least one of R³ and R⁴ is hydrogen; R⁵ and R⁶ are eachindependently selected from hydrogen; halogen; amino; C₁₋₅ alkyl,optionally substituted with at least one substituent, selected fromhalogen, hydroxy, C₁₋₃ (halo)alkoxy and C₃₋₆ (halo)cycloalkyl; C₁₋₅alkoxy, optionally substituted with at least one substituent, selectedfrom hydroxy, halogen, C₁₋₃ (halo)alkoxy, and C₃₋₆ (halo)cycloalkyl, andC₃₋₆ cycloalkyl, optionally substituted with at least one substituent,selected from hydroxy, halogen, C₁₋₃ (halo)alkyl and C₁₋₃ (halo)alkoxy;and R⁷ is hydrogen; C₁₋₅ alkyl, optionally substituted with at least onesubstituent, selected from halogen, hydroxy, C₁₋₃ (halo)alkoxy and C₃₋₆(halo)cycloalkyl; or C₃₋₆ cycloalkyl, optionally substituted with atleast one substituent, selected from hydroxy, halogen, C₁₋₃ (halo)alkyland C₁₋₃ (halo)alkoxy.
 2. The compound of claim 1, wherein n is
 1. 3.The compound of claim 1, wherein at least one of R¹ and R² is nothydrogen.
 4. The compound of claim 2, wherein at least one of R¹ and R²is not hydrogen.
 5. The compound of claim 1, wherein at least one of R¹and R² is selected from F, Cl, Br, C₁₋₄ (halo)alkyl, C₃₋₆(halo)cycloalkyl, C₁₋₃ (halo)alkoxy, C₁₋₃ (halo)alkoxy-C₁₋₃ (halo)alkyl,C₃₋₆ (halo)cycloalkyl-C₁₋₃ (halo)alkyl, and C₃₋₆ (halo)cycloalkyl-C₁₋₃(halo)alkoxy and wherein R³ and R⁴ are each independently selected fromhydrogen, F, Cl, Br, and C₁₋₃ (halo)alkyl, with the proviso that atleast one of R³ and R⁴ is hydrogen.
 6. The compound of claim 1, whereinR³ and R⁴ are each independently selected from hydrogen, F, Cl, Br, andC₁₋₃ (halo)alkyl, with the proviso that at least one of R³ and R⁴ ishydrogen.
 7. The compound of claim 1, wherein: Het is selected from

wherein: R⁵ and R⁶ are each independently selected from hydrogen, F, Cl,amino, C₁₋₃ alkyl, optionally substituted with at least one substituentselected from halogen, hydroxy, and C₁₋₃ (halo)alkoxy, C₁₋₃(halo)alkoxy, C₃₋₆ (halo)cycloalkyl, and C₃₋₆(halo)cycloalkyl-C₁₋₃(halo)alkyl; and R⁷ is hydrogen, C₁₋₃ alkyl,optionally substituted with at least one substituent, selected fromhalogen, hydroxy, C₁₋₃ (halo)alkoxy and C₃₋₆ (halo)cycloalkyl, or C₁₋₆cycloalkyl, optionally substituted with at least one substituent,selected from hydroxy, halogen, C₁₋₃ (halo)alkyl and C₁₋₃ (halo)alkoxy.8. The compound of claim 1, wherein: n is 1, R¹ and R² are eachindependently selected from F, Cl, C₁₋₂ (halo)alkyl, and C₁₋₂(halo)alkoxy; Het is selected from

R³ and R⁴ are each independently selected from hydrogen, F, and Cl, withthe proviso that at least one of R³ and R⁴ is hydrogen; R⁵ and R⁶ areeach independently selected from hydrogen, C₁₋₃ (halo)alkyl, C₃₋₆(halo)cycloalkyl, C₃₋₆ (halo)cycloalkyl, and C₃₋₆(halo)cycloalkyl-C₁₋₃(halo)alkyl; and R⁷ is hydrogen, C₁₋₃ alkyl,optionally substituted with at least one substituent, selected fromhalogen, hydroxy, C₁₋₃ (halo)alkoxy and C₃₋₆ (halo)cycloalkyl, C₃₋₅cycloalkyl, optionally substituted with at least one substituent,selected from hydroxy, halogen, C₁₋₃ (halo)alkyl and C₁₋₃ (halo)alkoxy.9. The compound of claim 1 selected from the group consisting:4-[2-[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-methylpyrazole,5-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-ethylpyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1-ethylpyrazol-4-yl)ethyl]pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-(1-ethylpropyl)-pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-cyclopentyl-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-[(1methylpyrazol-4-yl)methyl]pyrazole,4-[3-chloro-5-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,1,3-dimethyl-5-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,1-methyl-3-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,3-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-[4-chloro-3-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-[2-[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,4-[3-chloro-5-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,5-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole,4-[2-[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-ethyl-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole,4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethyl)-5-fluoro-phenyl]-1-[2-(1H-pyrazol-3-ylmethyl]pyrazole,1,3-dimethyl-5-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,1-methyl-3-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,1-methyl-3-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,1,3-dimethyl-5-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-yl]methyl]-1-methyl-pyrazole,4-(4-fluoro-3-methyl-phenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,5-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,3-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,5-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,3-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-(3-cyclopropylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-(3-methylsulfonylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,1-methyl-4-[[4-(3-methylsulfonylphenyl)pyrazol-1-yl]methyl]-pyrazole,pentafluoro-[3-[1-(1H-pyrazol-3-ylmethyl)pyrazol-4-yl]]phenyl]-sulfane,4-[2-[4-(4-chlorophenyl)-pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,5-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1-methyl-pyrazole,4-(4-chlorophenyl)-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,4-(4-chlorophenyl)-1-(1H-pyrazol-3-ylmethyl)pyrazole,4-(4-chlorophenyl)-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,3-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,5-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,1-methyl-3-[(4-phenylpyrazol-1-yl)methyl]pyrazole,1,3-dimethyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole, and1-methyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole; and pharmaceuticallyacceptable salt, solvate, polymorph, or N-oxide thereof.
 10. Thecompound of claim 1 selected from the group consisting of:4-[[4-(3-difluoromethoxy-4-chloro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,4-[[4-(3-difluoromethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,4-[[4-(3-(1,1-difluoroethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,3-[[4-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazole,3-[[4-(3-(1,1-difluoroethyl)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazole,and 3-[[4-(3-(difluoromethoxy)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazoleand pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof.
 11. The compound of claim 1 selected from the group consistingof:4-(4-chloro-3-(difluoromethyl)phenyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-pyrazole,4-(4-chlorophenyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-pyrazole,4-(3,4-dichlorophenyl)-2′-methyl-2′H-1,3′-bipyrazole,4-(3-chloro-4-fluorophenyl)-2′-methyl-2′H-1,3′-bipyrazole,2-((4-(4-chlorophenyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine,3-(3-(difluoromethyl)-4-fluorophenyl)-1-((5-((4-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazol-1-yl)methyl)-1H-pyrazol-3-yl)methyl)-1H-pyrazole,and 2-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)pyridine;and pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof.
 12. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 or pharmaceutically acceptablesalt, solvate, polymorph, or N-oxide thereof, and at least onepharmaceutically acceptable excipient.
 13. The pharmaceuticalcomposition of claim 12, further comprising a second active ingredient.14. A method of treating a disease, disorder or condition associatedwith NMDA receptor hyperactivity comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, polymorph, orN-oxide thereof.
 15. The method of claim 14, wherein the disorder,disease or condition is selected from the group consisting of: bipolardisorder, major depressive disorder, and treatment-resistant depression.16. A method for treating a disease, disorder or condition mediated byGluN2B receptors comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof.
 17. The method of claim 16, wherein the disorder, disease orcondition is selected from the group consisting of treatment resistantdepression and major depressive disorder.
 18. A method of treating adisease, disorder or condition in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt, solvate,polymorph, or N-oxide thereof.
 19. The method of claim 18, wherein thedisease or disorder is a neurologic or psychiatric disorder.
 20. Themethod of claim 19, wherein the disease or disorder is selected from thegroup consisting of a mood disorder; a stress-related disorder andneurodegeneration.
 21. The method of claim 20, wherein thestress-related disorder is an anxiety disorder.
 22. The method of claim19 wherein the neurologic disorder is epilepsy.
 23. The method of claim17, wherein the disorder, disease or condition is treatment resistantdepression.
 24. The method of claim 17, wherein the disorder, disease orcondition is major depressive disorder.
 25. The compound of claim 1selected from the group consisting of:4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethy)pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole;4-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole;4-[4-Chloro-3-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole;4-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole;and4-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole;and pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof.
 26. A method of treating a disorder in a patient comprisingadministering to a patient in need thereof a compound of claim 25wherein the disorder is selected from the group consisting of bipolardisorder, major depressive disorder, and treatment-resistant depression.27. A method of claim 26 wherein the disorder is major depressivedisorder.
 28. A method of treating a disorder in a patient comprisingadministering to a patient in need thereof a compound of claim 25wherein the disorder is epilepsy.
 29. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound selectedfrom the group consisting of:4-[2-[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-methylpyrazole,5-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-ethylpyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[2-(1-ethylpyrazol-4-yl)ethyl]pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-(1-ethylpropyl)-pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-1-cyclopentyl-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,3-[[4-[4-chloro-3-(difluoromethoxy)phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[4-chloro-3-(difluoromethoxy)phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-[(1methylpyrazol-4-yl)methyl]pyrazole,4-[3-chloro-5-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,1,3-dimethyl-5-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,1-methyl-3-[[4-[3-(trifluoromethoxy)phenyl]pyrazol-1-yl]methyl]pyrazole,3-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-[4-chloro-3-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-[2-[4-[4-chloro-3-(difluoromethyl)phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,4-[3-chloro-5-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole,5-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole,4-[2-[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[2-(1H-pyrazol-4-yl)ethyl]pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-1-ethyl-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyl-1H-pyrazol-5-yl)methyl]pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-ethyl-1H-pyrazole,3-[[4-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-5-propyl-1H-pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole,4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,4-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole,4-[3-(difluoromethyl)-5-fluoro-phenyl]-1-[2-(1H-pyrazol-3-ylmethyl]pyrazole,1,3-dimethyl-5-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,1-methyl-3-[[4-[3-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,1-methyl-3-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,1,3-dimethyl-5-[[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]methyl]pyrazole,5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,5-[[4-(3-fluoro-4-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(4-fluoro-3-methyl-phenyl)pyrazol-yl]methyl]-1-methyl-pyrazole,4-(4-fluoro-3-methyl-phenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,5-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(4-chloro-3-methyl-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,3-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-chloro-3-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(3-chloro-4-fluoro-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(3,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,5-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(2,4-dichlorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,3-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-fluoro-2-methoxy-phenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,4-(3-cyclopropylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,4-(3-methylsulfonylphenyl)-1-(1H-pyrazol-3-ylmethyl)-pyrazole,1-methyl-4-[[4-(3-methylsulfonylphenyl)pyrazol-1-yl]methyl]-pyrazole,pentafluoro-[3-[1-(1H-pyrazol-3-ylmethyl)pyrazol-4-yl]]phenyl]-sulfane,4-[2-[4-(4-chlorophenyl)-pyrazol-1-yl]ethyl]-3,5-dimethyl-1H-pyrazole,5-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(4-chlorophenyl)-pyrazol-1-yl]methyl]-1-methyl-pyrazole,4-(4-chlorophenyl)-1-[(2-methylpyrazol-3-yl)methyl]pyrazole,4-(4-chlorophenyl)-1-(1H-pyrazol-3-ylmethyl)pyrazole,4-(4-chlorophenyl)-1-[(1-methylpyrazol-4-yl)methyl]pyrazole,3-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(4-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,5-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3-bromophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,5-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1,3-dimethyl-pyrazole,3-[[4-(3,5-difluorophenyl)pyrazol-1-yl]methyl]-1-methyl-pyrazole,1-methyl-3-[(4-phenylpyrazol-1-yl)methyl]pyrazole,1,3-dimethyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole, and1-methyl-5-[(4-phenylpyrazol-1-yl)methyl]pyrazole; and andpharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof, and at least one pharmaceutically acceptable excipient.
 30. Apharmaceutical composition comprising a therapeutically effective amountof a compound selected from the group consisting of:4-[[4-(3-Difluoromethoxy-4-chloro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,4-[[4-(3-Difluoromethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,4-[[4-(3-(1,1-Difluoroethyl-4-fluoro-phenyl)pyrazol-1-yl]methyl]-3,5-dimethyl-1H-pyrazole,3-[[4-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazole,3-[[4-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazol-1-yl]methyl]-4-ethyl-1H-pyrazole,3-[[4-(3-(1,1-Difluoroethyl)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazole,and 3-[[4-(3-(Difluoromethoxy)-phenyl)pyrazol-1-yl]methyl]-1H-pyrazole;and pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof, and at least one pharmaceutically acceptable excipient.
 31. Apharmaceutical composition comprising a therapeutically effective amountof a compound selected from the group consisting of:4-(4-Chloro-3-(difluoromethyl)phenyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-pyrazole,4-(4-Chlorophenyl)-1-(1-ethyl-1H-imidazol-5-yl)methyl)-1H-pyrazole,4-(3,4-Dichlorophenyl)-2′-methyl-2′H-1,3′-bipyrazole,4-(3-Chloro-4-fluorophenyl)-2′-methyl-2′H-1,3′-bipyrazole,2-((4-(4-Chlorophenyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine,3-(3-(Difluoromethyl)-4-fluorophenyl)-1-((5-((4-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazol-1-yl)methyl)-1H-pyrazol-3-yl)methyl)-1H-pyrazole,and 2-(1-((1-Methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)pyridine;and pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof, and at least one pharmaceutically acceptable excipient.
 32. Apharmaceutical composition comprising a therapeutically effective amountof a compound selected from the group consisting of:4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(1-methylpyrazol-4-yl)methyl]pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(2-methylpyrazol-3-yl)methyl]pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-1H-pyrazol-4-yl)methyl]pyrazole;4-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-ethyl-1H-pyrazol-4-yl)methyl]pyrazole;4-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)-pyrazole;4-[4-Chloro-3-(difluoromethyl)phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole;4-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole;and4-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-3-ylmethyl)pyrazole;and pharmaceutically acceptable salt, solvate, polymorph, or N-oxidethereof, and at least one pharmaceutically acceptable excipient.